Methods to facilitate transmission of large molecules across the blood-brain, blood-eye, and blood-nerve barriers

ABSTRACT

A method for delivering a biologic to a human, comprising administering said biologic parenterally into the perispina! space of said human without direct intrathecal injection and positioning said human in a Trendelenburg position.

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 12/568,661,filed Oct. 19, 2009, which is a continuation of application Ser. No.11/601,799, filed Nov. 17, 2006, now U.S. Pat. No. 7,629,311, which is acontinuation-in-part of application Ser. No. 11/016,047, filed Dec. 18,2004 now U.S. Pat. No. 7,214,658. All of the above patents and patentapplications included in this paragraph are incorporated by reference intheir entirety herein.

This application is also related to provisional U.S. patent application60/662,744 entitled “Methods of Use of the Vertebral Venous System toDeliver Biologics to the CNS” filed Mar. 16, 2005. In addition to theabove, this application claims priority from U.S. provisionalapplication 60/585,735, filed Jul. 6, 2004; U.S. provisional application60/738,331, entitled “Methods to facilitate transmission of golimumaband other therapeutic molecules across the blood-brain barrier”, filedNov. 18, 2005; and U.S. provisional application entitled “Methods tofacilitate transmission of golimumab and other therapeutic moleculesacross the blood-brain, blood-eye, and blood-nerve barriers”, 60/760,236, filed Jan. 18, 2006, all of which are hereby incorporated byreference in their entirety herein. The use of perispinal administrationof cytokine antagonists to treat neurological disorders is discussed inUS patent application 20030049256 of this inventor. The use ofperispinal administration without direct intrathecal injection and thevertebral venous system to deliver large molecules to the brain, theeye, and the auditory apparatus are discussed in provisional patentapplications 60/585,735 filed Jul. 6, 2004; 60/659,414 filed Mar. 9,2005; 60/662,744 filed Mar. 17, 2005; and 60/669,022, filed Apr. 7,2005. All of the above patents and patent applications included in thisparagraph are incorporated by reference in their entirety herein.

2. FIELD OF THE INVENTION

This application concerns novel methods which enable golimumab, ananti-TNF biologic and other molecules, to cross the blood-brain barrier,the blood-eye barrier, and/or the blood-nerve barrier and therefore beof therapeutic use in humans and other mammals. These methods involveperispinal administration of each of these molecules without directintrathecal injection. Perispinal administration is defined asadministration of the molecule into the anatomic area within 10 cm ofthe spine. Perispinal administration results in absorption of golimumabinto the vertebral venous system. The vertebral venous system is capableof transporting molecules to the head, including into the brain, theeye, the retina, the auditory apparatus, the cranial nerves or the head,via retrograde venous flow, thereby bypassing the blood-brain barrierand delivering the molecules to the brain, the eye, the retina, theauditory apparatus, the cranial nerves or the head.

This method may be utilized for a wide variety of large molecules,including, but not limited to, recombinant DNA therapeutics, otherbiologics, monoclonal antibodies, fusion proteins, monoclonal antibodyfragments, hormones, cytokines, anti-cytokines, interleukins,anti-interleukins, interferons, colony-stimulating factors, cancerchemotherapeutic agents, growth factors, anti-virals and antibiotics.

In addition the methods of the present invention may be used to delivermolecules with a MW less than 2,000 daltons to the brain and otherstructures of the head more efficiently than if delivered systemically,and these methods utilizing these molecules are also to be considered apart of this invention.

In addition to human use, these methods may be used to treat othermammals, including horses, dogs, and cats.

This method may be used for delivery for humans or other mammals withneurodegenerative diseases, including Alzheimer's Disease and otherforms of dementia, including both Alzheimer's-related dementia andnon-Alzheimer dementias; Parkinson's Disease, amyotrophic lateralsclerosis; for eye disorders or diseases including, but not limited to,macular degeneration, diabetic retinopathy, sympathetic opthalmia andretinitis pigmentosa; disorders of hearing, including, but not limitedto sensorineural hearing loss or presbycusis; central nervous system(CNS) tumors, including tumors of the brain; for other diseases ordisorders of the brain, including, but not limited to vascular disorderssuch as stroke, transient ischemic attack, vascular dementia, andcerebrovascular disease; infectious diseases of the CNS, including viraland bacterial infections; for sciatica, cervical radiculopathy, andother forms of disc-related pain; for low back pain; other diseases ordisorders involving the spine, the spinal cord, the spinal nerve roots,the brain, eyes, auditory apparatus, or other structures of the head.

The use of cytokine antagonists to treat neurological disorders is thesubject of several previous patents of this inventor, including U.S.Pat. Nos. 6,015,557, 6,177,077, 6,419,934 6,419,944, 6,423,321,6,428,787, 6,537,549, 6,623,736 and US patent applications 20030049256and U.S. patent application Ser. No. 11/016,047, filed Dec. 18, 2004,entitled “Methods of use of etanercept to improve human cognitivefunction”, and provisional U.S. patent application 60/585,735, filedJul. 6, 2004. These issued patents, patent applications, and provisionalpatent applications are incorporated in their entirety herein. Thisinvention includes further applications of these ideas.

The adverse biologic effects of excess TNF can be reduced by the use ofbiologic inhibitors of TNF. These inhibitors can be divided into twobroad categories: monoclonal antibodies and their derivatives; and TNFbinding biologics which are not antibody based. In the first categorybelong golimumab, also known as CNTO-148 (Centocor, Schering-Plough),infliximab (Remicade®, Centocor), adalimumab (Humira®, Abbott), and CDP870 (Celltech). The second category includes etanercept, soluble TNFreceptor type 1, pegylated soluble TNF receptor type 1 (Amgen) andonercept (Serono). Etanercept has a serum half life of approximately 4.8days when administered to patients with rheumatoid arthritis on achronic basis; onercept has a serum half-life which is considerablyshorter, and it is usually administered at least three times weekly whenused to treat systemic illnesses.

Golimumab has many biologic effects. Golimumab, for example, in additionto being a potent anti-inflammatory also has important anti-apoptoticeffects which may be of particular importance in treating neurologicaldisorders, such as certain forms of dementia, where apoptosis plays apathogenetic role.

Antibodies (immunoglobulins) are proteins produced by one class oflymphocytes (B cells) in response to specific exogenous foreignmolecules (antigens). Monoclonal antibodies (mAB), identicalimmunoglobulin copies which recognize a single antigen, are derived fromclones (identical copies) of a single B cell. This technology enableslarge quantities of an immunoglobulin with a specific target to be massproduced.

Monoclonal antibodies with a high affinity for a specific cytokine willtend to reduce the biologic activity of that cytokine. Substances whichreduce the biologic effect of a cytokine can be described in any of thefollowing ways: as a cytokine blocker; as a cytokine inhibitor; or as acytokine antagonist. In this patent, the terms blocker, inhibitor, andantagonist are used interchangeably with respect to cytokines.

Advances in biotechnology have resulted in improved molecules ascompared to simply using monoclonal antibodies. One such molecule is CDP870 which, rather than being a monoclonal antibody, is a new type ofmolecule, that being an antibody fragment. By removing part of theantibody structure, the function of this molecule is changed so that itacts differently in the human body. Another new type of molecule,distinct from monoclonal antibodies and soluble receptors, is a fusionprotein. One such example is etanercept. This molecule has a distinctfunction which acts differently in the human body than a simple solublereceptor or receptors.

Monoclonal antibodies, fusion proteins, and all of the specificmolecules discussed above under the categories of TNF antagonists andinterleukin antagonists are considered biologics, in contrast to drugsthat are chemically synthesized. For the purpose of this patent abiologic is defined as a molecule produced through recombinant DNAtechnology which is derived from the DNA of a living source. The livingsources may include humans, other animals, or microorganisms. Thebiologics mentioned above are manufactured using biotechnology, whichusually involves the use of recombinant DNA technology. Cytokineantagonists are one type of biologic. Biologics are regulated through aspecific division of the FDA.

Cytokine antagonists can take several forms. They may be monoclonalantibodies (defined above). They may be a monoclonal antibody fragment.They may take the form of a soluble receptor to that cytokine Solublereceptors freely circulate in the body. When they encounter their targetcytokine they bind to it, effectively inactivating the cytokine, sincethe cytokine is then no longer able to bind with its biologic target inthe body. An even more potent antagonist consists of two solublereceptors fused together to a specific portion of an immunoglobulinmolecule (Fc fragment). This produces a dimer composed of two solublereceptors which have a high affinity for the target, and a prolongedhalf-life. This new molecule is called a fusion protein. An example ofthis new type of molecule, called a fusion protein, is etanercept(Enbrel®).

TNF, a naturally occurring cytokine present in humans and other mammals,plays a key role in the inflammatory response, in the immune responseand in the response to infection. TNF is formed by the cleavage of aprecursor transmembrane protein, forming soluble molecules whichaggregate in vivo to form trimolecular complexes. These complexes thenbind to receptors found on a variety of cells. Binding produces an arrayof pro-inflammatory effects, including release of other pro-inflammatorycytokines, including IL-6, IL-8, and IL-1; release of matrixmetalloproteinases; and up regulation of the expression of endothelialadhesion molecules, further amplifying the inflammatory and immunecascade by attracting leukocytes into extravascular tissues.

Golimumab is currently in clinical development byCentocor/Schering-Plough for treatment of rheumatoid arthritis, withpotential applications for uveitis, asthma, and Crohn's Disease. It maybe described as a immunoglobulin G1, anti-(human tumor necrosis factorα) (human monoclonal CNTO 148 γ1-chain), disulfide with human monoclonalCNTO 148 K-chain), dimer, and has CAS Registry number 476181-74-5. It isa fully human anti-TNF monoclonal antibody.

Etanercept (Enbrel®, Amgen/Immunex), golimumab, infliximab (Remicade®,Centocor), adalimumab (Humira®, Abbott), CDP 870, and onercept arepotent and selective inhibitors of TNF. CDP 870, golimumab and onerceptare in clinical development. Etanercept, adalimumab, and infliximab areFDA approved for chronic systemic use to treat rheumatoid arthritis andcertain other chronic inflammatory disorders. Golimumab has a molecularweight of approximately 147,000 daltons.

Bevacizumab (Avastin™, Genentech) is a recombinant humanized monoclonalIgG1 antibody that binds to and inhibits the biologic activity of humanvascular endothelial growth factor (VEGF) and which may be useful forthe treatment of various malignancies. Bevacizumab has a molecularweight of 149,000 daltons and is therefore too large to readily crossthe blood-brain barrier if administered systemically.

Anti-amyloid antibodies of the present invention include immune globulinderived from human plasma, including Gammagard™ and Kiovig™ brands ofIVIG produced by Baxter and other brands of IVIG; antibodies againstbeta-amyloid; and, specifically, Bapineuzumab, a humanized monoclonalantibody to A-beta currently being jointly developed by Elan and Wyeth.

Etanercept, one of the molecules of this invention, can also bedesignated as TNFR:Fc because it is a dimeric fusion protein consistingof two soluble TNF receptors fused to a Fc portion of an immunoglobulinmolecule. This fusion protein functions in a manner quite distinct froma simple soluble TNF receptor. Soluble TNF receptors are normallypresent in the human body. But the use of these soluble TNF receptors astherapeutic agents for the treatment of the conditions of considerationin this patent is made impractical by their extremely short half-lifeand therefore their limited biologic activity. The present inventionutilizing etanercept is therefore distinguished from an inventionspecifying the use of a soluble TNF receptor. It is incorrect andimprecise to describe etanercept as a soluble TNF receptor because thisis an incorrect description of its complex structure and omitscharacteristics of etanercept which are absolutely essential to itsfunction. This is further underscored by the developmental history ofetanercept. In its first iteration the precursor molecule to etanerceptwas produced with a single TNF receptor fused to an immunoglobulinfragment. The biologic activity of this molecule was poor. Therefore notonly is etanercept distinguished from a soluble TNF receptor, it is alsodistinguished from a TNF-binding fusion protein which contains therecombinant DNA sequence of only a single soluble TNF receptor. Theunique structure of etanercept, containing a dimer (two) soluble TNFreceptors fused to an Fc portion of an immunoglobulin molecule, isnecessary for the proper performance of the present invention. Sinceetanercept has the molecular structure of a fusion protein it is thusquite distinct from both onercept, soluble TNF receptor type 1 andpegylated soluble TNF receptor type 1.

The vertebral venous system can also be used to deliver other types oftherapeutic agents to the cerebral cortex, eye, retina, cerebellum,brainstem, eighth cranial nerve, cochlea, inner ear, and cerebrospinalfluid. These therapeutic agents include pharmacologic agents, othercytokine antagonists, and growth factors which affect neuronal function,or the immune response impacting neuronal function, including, but notlimited to: interleukins including IL-1, IL-2, IL-4, IL-6, IL-10, andIL-13; interleukin 1 antagonists, such as IL-1 RA (Kineret®, Amgen) andIL-1 Trap; fusion proteins, such as IL-10 fusion protein and etanercept(Enbrel®, Immunex); human growth hormone and related biologics(recombinant human growth hormone, Humatrope® (somatropin) Eli Lilly &Co., Nutropin®/Nutropin AQ® (somatropin), Geref® (sermorelin) Serono,and Protropin® (somatrem) Genentech)); BDNF; erythropoietin (Epogen®(epoetin alpha) Amgen, Procrit® (epoetin alpha) Johnson & Johnson);G-CSF (Neupogen® (filgrastim), Amgen); GM-CSF; Intron® A (interferonalfa-2b) Schering-Plough; Avonex® (interferon beta-1a) Biogen;bevacizumab (Avastin™, Genentech); pegaptanib, ranibizumab, and otherbiologic VEGF antagonists; alefacept (LFA-3/IgG1 human fusion protein,Amevive® Biogen); Epidermal growth factor; anti-EGF (ABX-EGF, Abgenix);transforming growth factor-beta 1 (TGF-beta 1); NGF, or other compoundswith CNS, vascular or immune therapeutic activity. Perispinal deliveryis particularly advantageous when biologics, such as etanercept, whichprofoundly affect neuronal function, are administered because of theirefficacy at extremely low concentration (high biologic potency).

This method may be used for delivery for humans or other mammals withneurodegenerative diseases, including Alzheimer's Disease, other formsof Alzheimer-related dementia, non-Alzheimer dementia, Parkinson'sDisease, and amyotrophic lateral sclerosis; for eye disorders ordiseases including, but not limited to, macular degeneration, diabeticretinopathy, sympathetic opthalmia and retinitis pigmentosa; disordersof hearing, including, but not limited to sensorineural hearing loss orpresbycusis; central nervous system (CNS) tumors, including tumors ofthe brain; for other diseases or disorders of the brain, including, butnot limited to vascular disorders such as stroke, transient ischemicattack, vascular dementia, and cerebrovascular disease; infectiousdiseases of the CNS, including viral and bacterial infections; forsciatica, cervical radiculopathy, and other forms of disc-related pain;for low back pain; other diseases or disorders involving the spine, thespinal cord, the spinal nerve roots, the brain, eyes, auditoryapparatus, or other structures of the head.

3. BACKGROUND OF THE INVENTION

The following description of the background of the invention is providedas an aid to understanding the invention and is not admitted to describeor constitute prior art to the invention.

This application concerns novel methods which enable golimumab, ananti-TNF biologic and other molecules, to cross the blood-brain barrier,the blood-eye barrier, and/or the blood-nerve barrier and therefore beof therapeutic use in humans and other mammals. Included among thesemethods are those which involve perispinal administration of golimumabwithout direct intrathecal injection. In addition, additional methodsinvolve the perispinal administration of other molecules, as detailedherein. Perispinal administration is defined as administration of themolecule into the anatomic area within 10 cm of the spine. Perispinaladministration results in absorption of golimumab or other moleculesgiven by perispinal administration, into the vertebral venous system.The vertebral venous system is capable of transporting therapeuticmolecules to the head, including into the brain, the eye, the retina,the auditory apparatus, the cranial nerves or the head, via retrogradevenous flow, thereby bypassing the blood-brain barrier and deliveringthe molecules to the brain, the eye, the retina, the auditory apparatus,the cranial nerves or the head.

This method may be utilized for a wide variety of large molecules,including, but not limited to, recombinant DNA therapeutics, otherbiologics, monoclonal antibodies, fusion proteins, monoclonal antibodyfragments, hormones, cytokines, anti-cytokines, interleukins,anti-interleukins, interferons, colony-stimulating factors, cancerchemotherapeutic agents, growth factors, anti-virals and antibiotics.

In addition the methods of the present invention may be used to delivermolecules with a MW less than 2,000 daltons to the brain and otherstructures of the head more efficiently than if delivered systemically,and these methods utilizing these smaller molecules are also to beconsidered a part of this invention.

In addition to human use, these methods may be used to treat othermammals, including horses, dogs, and cats.

This method may be used for delivery for humans or other mammals withneurodegenerative diseases, including Alzheimer's Disease, Parkinson'sDisease, amyotrophic lateral sclerosis; for eye disorders or diseasesincluding, but not limited to, macular degeneration, diabeticretinopathy, sympathetic opthalmia and retinitis pigmentosa; disordersof hearing, including, but not limited to sensorineural hearing loss orpresbycusis; central nervous system (CNS) tumors, including tumors ofthe brain; for other diseases or disorders of the brain, including, butnot limited to vascular disorders such as stroke, transient ischemicattack, vascular dementia, and cerebrovascular disease; infectiousdiseases of the CNS, including viral and bacterial infections; forsciatica, cervical radiculopathy, and other forms of disc-related pain;for low back pain; other diseases or disorders involving the spine, thespinal cord, the spinal nerve roots, the brain, eyes, auditoryapparatus, or other structures of the head.

The use of cytokine antagonists to treat neurological disorders is thesubject of several previous patents of this inventor, including U.S.Pat. Nos. 6,015,557, 6,177,077, 6,419,934 6,419,944, 6,423,321,6,428,787, 6,537,549, 6,623,736 and US patent applications 20030049256and U.S. patent application Ser. No. 11/016,047, filed Dec. 18, 2004,entitled “Methods of use of etanercept to improve human cognitivefunction”, and provisional U.S. patent application 60/585,735, filedJul. 6, 2004. These issued patents, patent applications, and provisionalpatent applications are incorporated in their entirety herein. Thisinvention includes further applications of these ideas.

The adverse biologic effects of excess TNF can be reduced by the use ofbiologic inhibitors of TNF. These inhibitors can be divided into twobroad categories: monoclonal antibodies and their derivatives; and TNFbinding biologics which are not antibody based. In the first categorybelong golimumab, also known as CNTO-148 (Centocor, Schering-Plough),infliximab (Remicade®, Centocor), adalimumab (Humira®, Abbott), and CDP870 (Celltech). The second category includes etanercept, soluble TNFreceptor type 1, pegylated soluble TNF receptor type 1 (Amgen) andonercept (Serono). Etanercept has a serum half life of approximately 4.8days when administered to patients with rheumatoid arthritis on achronic basis; onercept has a serum half-life which is considerablyshorter, and it is usually administered at least three times weekly whenused to treat systemic illnesses.

Golimumab has many biologic effects. Golimumab, for example, in additionto being a potent anti-inflammatory also has important anti-apoptoticeffects which may be of particular importance in treating neurologicaldisorders, such as certain forms of dementia, where apoptosis plays apathogenetic role.

Antibodies (immunoglobulins) are proteins produced by one class oflymphocytes (B cells) in response to specific exogenous foreignmolecules (antigens). Monoclonal antibodies (mAB), identicalimmunoglobulin copies which recognize a single antigen, are derived fromclones (identical copies) of a single B cell. This technology enableslarge quantities of an immunoglobulin with a specific target to be massproduced.

Monoclonal antibodies with a high affinity for a specific cytokine willtend to reduce the biologic activity of that cytokine Substances whichreduce the biologic effect of a cytokine can be described in any of thefollowing ways: as a cytokine blocker; as a cytokine inhibitor; or as acytokine antagonist. In this patent, the terms blocker, inhibitor, andantagonist are used interchangeably with respect to cytokines.

Advances in biotechnology have resulted in improved molecules ascompared to simply using monoclonal antibodies. One such molecule is CDP870 which, rather than being a monoclonal antibody, is a new type ofmolecule, that being an antibody fragment. By removing part of theantibody structure, the function of this molecule is changed so that itacts differently in the human body. Another new type of molecule,distinct from monoclonal antibodies and soluble receptors, is a fusionprotein. One such example is etanercept. This molecule has a distinctfunction which acts differently in the human body than a simple solublereceptor or receptors.

Monoclonal antibodies, fusion proteins, and all of the specificmolecules discussed above under the categories of TNF antagonists andinterleukin antagonists are considered biologics, in contrast to drugsthat are chemically synthesized. For the purpose of this patent abiologic is defined as a molecule produced through recombinant DNAtechnology which is derived from the DNA of a living source. The livingsources may include humans, other animals, or microorganisms. Thebiologics mentioned above are manufactured using biotechnology, whichusually involves the use of recombinant DNA technology. Cytokineantagonists are one type of biologic. Biologics are regulated through aspecific division of the FDA.

Cytokine antagonists can take several forms. They may be monoclonalantibodies (defined above). They may be a monoclonal antibody fragment.They may take the form of a soluble receptor to that cytokine Solublereceptors freely circulate in the body. When they encounter their targetcytokine they bind to it, effectively inactivating the cytokine, sincethe cytokine is then no longer able to bind with its biologic target inthe body. An even more potent antagonist consists of two solublereceptors fused together to a specific portion of an immunoglobulinmolecule (Fc fragment). This produces a dimer composed of two solublereceptors which have a high affinity for the target, and a prolongedhalf-life. This new molecule is called a fusion protein. An example ofthis new type of molecule, called a fusion protein, is etanercept(Enbrel®).

TNF, a naturally occurring cytokine present in humans and other mammals,plays a key role in the inflammatory response, in the immune responseand in the response to infection. TNF is formed by the cleavage of aprecursor transmembrane protein, forming soluble molecules whichaggregate in vivo to form trimolecular complexes. These complexes thenbind to receptors found on a variety of cells. Binding produces an arrayof pro-inflammatory effects, including release of other pro-inflammatorycytokines, including IL-6, IL-8, and IL-1; release of matrixmetalloproteinases; and up regulation of the expression of endothelialadhesion molecules, further amplifying the inflammatory and immunecascade by attracting leukocytes into extravascular tissues.

Golimumab is currently in clinical development byCentocor/Schering-Plough for treatment of rheumatoid arthritis, withpotential applications for uveitis, asthma, and Crohn's Disease. It maybe described as a immunoglobulin G1, anti-(human tumor necrosis factorα) (human monoclonal CNTO 148 γ1-chain), disulfide with human monoclonalCNTO 148 K-chain), dimer, and has CAS Registry number 476181-74-5. It isa fully human anti-TNF monoclonal antibody.

Etanercept (Enbrel®, Amgen/Immunex), golimumab, infliximab (Remicade®,Centocor), adalimumab (Humira®, Abbott), CDP 870, and onercept arepotent and selective inhibitors of TNF. CDP 870, golimumab and onerceptare in clinical development. Etanercept, adalimumab, and infliximab areFDA approved for chronic systemic use to treat rheumatoid arthritis andcertain other chronic inflammatory disorders. Golimumab has a molecularweight of approximately 147,000 daltons.

Bevacizumab (Avastin™, Genentech) is a recombinant humanized monoclonalIgG1 antibody that binds to and inhibits the biologic activity of humanvascular endothelial growth factor (VEGF) and which may be useful forthe treatment of various malignancies. Bevacizumab has a molecularweight of 149,000 daltons and is therefore too large to readily crossthe blood-brain barrier if administered systemically.

Etanercept can also be designated as TNFR:Fc because it is a dimericfusion protein consisting of two soluble TNF receptors fused to a Fcportion of an immunoglobulin molecule. This fusion protein functions ina manner quite distinct from a simple soluble TNF receptor. Soluble TNFreceptors are normally present in the human body. But the use of thesesoluble TNF receptors as therapeutic agents for the treatment of theconditions of consideration in this patent is made impractical by theirextremely short half-life and therefore their limited biologic activity.The present invention utilizing etanercept is therefore distinguishedfrom an invention specifying the use of a soluble TNF receptor. It isincorrect and imprecise to describe etanercept as a soluble TNF receptorbecause this is an incorrect description of its complex structure andomits characteristics of etanercept which are absolutely essential toits function. This is further underscored by the developmental historyof etanercept. In its first iteration the precursor molecule toetanercept was produced with a single TNF receptor fused to animmunoglobulin fragment. The biologic activity of this molecule waspoor. Therefore not only is etanercept distinguished from a soluble TNFreceptor, it is also distinguished from a TNF-binding fusion proteinwhich contains the recombinant DNA sequence of only a single soluble TNFreceptor. The unique structure of etanercept, containing a dimer (two)soluble TNF receptors fused to an Fc portion of an immunoglobulinmolecule, is necessary for the proper performance of the presentinvention. Since etanercept has the molecular structure of a fusionprotein it is thus quite distinct from both onercept, soluble TNFreceptor type 1 and pegylated soluble TNF receptor type 1.

The vertebral venous system can also be used to deliver other types oftherapeutic agents to the cerebral cortex, eye, retina, cerebellum,brainstem, eighth cranial nerve, cochlea, inner ear, and cerebrospinalfluid. These therapeutic agents include pharmacologic agents, othercytokine antagonists, and growth factors which affect neuronal function,or the immune response impacting neuronal function, including, but notlimited to: interleukins including IL-1, IL-2, IL-4, IL-6, IL-10, andIL-13; interleukin 1 antagonists, such as IL-1 RA (Kineret®, Amgen) andIL-1 Trap; fusion proteins, such as IL-10 fusion protein and etanercept(Enbrel®, Immunex); human growth hormone and related biologics(recombinant human growth hormone, Humatrope® (somatropin) Eli Lilly &Co., Nutropin®/Nutropin AQ® (somatropin), Geref® (sermorelin) Serono,and Protropin® (somatrem) Genentech)); BDNF; erythropoietin (Epogen®(epoetin alpha) Amgen, Procrit® (epoetin alpha) Johnson & Johnson);G-CSF (Neupogen® (filgrastim), Amgen); GM-CSF; Intron® A (interferonalfa-2b) Schering-Plough; Avonex® (interferon beta-1a) Biogen;bevacizumab (Avastin™, Genentech); pegaptanib, ranibizumab, and otherbiologic VEGF antagonists; alefacept (LFA-3/IgG1 human fusion protein,Amevive® Biogen); Epidermal growth factor; anti-EGF (ABX-EGF, Abgenix);transforming growth factor-beta 1 (TGF-beta 1); NGF, or other compoundswith CNS, vascular or immune therapeutic activity. Perispinal deliveryis particularly advantageous when biologics, such as etanercept, whichprofoundly affect neuronal function, are administered because of theirefficacy at extremely low concentration (high biologic potency).

This method may be used for delivery for humans or other mammals withneurodegenerative diseases, including Alzheimer's Disease, Parkinson'sDisease, amyotrophic lateral sclerosis; for eye disorders or diseasesincluding, but not limited to, macular degeneration, diabeticretinopathy, sympathetic opthalmia and retinitis pigmentosa; disordersof hearing, including, but not limited to sensorineural hearing loss orpresbycusis; central nervous system (CNS) tumors, including tumors ofthe brain; for other diseases or disorders of the brain, including, butnot limited to vascular disorders such as stroke, transient ischemicattack, vascular dementia, and cerebrovascular disease; infectiousdiseases of the CNS, including viral and bacterial infections; forsciatica, cervical radiculopathy, and other forms of disc-related pain;for low back pain; other diseases or disorders involving the spine, thespinal cord, the spinal nerve roots, the brain, eyes, auditoryapparatus, or other structures of the head.

Localized administration for the treatment of localized clinicaldisorders has many clinical advantages over the use of conventionalsystemic treatment. Locally administered medication after deliverydiffuses through local capillary, venous, arterial, and lymphatic actionto reach the therapeutic target. In addition local administration of alarge molecule, such as goliumumab, defined as a molecule with amolecular weight greater than or equal to 2,000 daltons, in the vicinityof the spine (perispinal administration) without direct intrathecalinjection has the key advantage of improved delivery of the molecule tothe brain and across the blood-brain barrier (BBB), with deliveryenhanced by transport via the vertebral venous system. Intrathecalinjection delivers the molecule into the cerebrospinal fluid (CSF), buthas disadvantages of possible infection, hemorrhage, and subsequent CSFleak.

The BBB is a physiologic barrier which separates the brain andcerebrospinal fluid from the blood. It consists of a layer of cellswhich comprise the cerebral capillary endothelium, the choroid plexusepithelium, and the arachnoid membranes, which are connected by tightjunctions (zonulae occludens). These tight junctions may be as much as100 times tighter than junctions of other capillary endothelium, andprevent molecules larger than about 600 daltons in molecular weight (MW)from traversing the BBB when the molecule is administered systemicallyi.e. by conventional subcutaneous, intramuscular, or intravenousinjection at an anatomic site remote from the spine.

The vertebral venous system (VVS) is an interconnected plexus of veinswhich surrounds the spinal cord and extends the entire length of thespine. This venous system provides a vascular route from the pelvis tothe cranium which richly involves the bone marrow of the spine and whichis functionally distinct from the systemic venous system. Firstdescribed by Willis in 1663, the functional significance of thevertebral venous system was largely unappreciated until the work ofBatson, who in 1940 proposed that this venous plexus provided the routeby which prostate cancer metastasizes to the vertebral column.Acceptance of Batson's proposal by the medical community has led to thedesignation of the vertebral venous system as Batson's Plexus. Althoughnow widely appreciated as a possible route by which cancer cells mayspread to the spine there have been no previous suggestions thatBatson's plexus may be of therapeutic usefulness. The use of Batson'splexus as route of delivery of biologics for clinical use, and as aroute for delivery of large molecules to the brain, the eye, the retina,the auditory apparatus, the cranial nerves or the head are inventions ofthe author. This patent is a continuation to the methods of use ofBatson's plexus to deliver therapeutic molecules to the nervous systemwhich has been previously proposed by the inventor, and incorporates theprevious patents and patent applications discussing this. In additionthis patent is related to provisional U.S. patent application 60/662,744entitled “Methods of Use of the Vertebral Venous System to DeliverBiologics to the CNS” filed Mar. 16, 2005, and application Ser. No.10/269,745, entitled “Cytokine antagonists for neurological andneuropsychiatric disorders”, filed Oct. 9, 2002, and each of thesepatent applications are hereby incorporated herein in their entirety.

Perispinal administration involves anatomically localized deliveryperformed so as to place the therapeutic molecule directly in thevicinity of the spine at the time of initial administration. For thepurposes of this patent, “in the vicinity of” is defined as within 10centimeters. Perispinal administration includes, but is not limited to,the following types of administration: parenteral; subcutaneous;intramuscular; or interspinous; and specifically includes the use ofinterspinous injection carried through the skin in the midline of theneck or back, directly overlying the spine. For the purposes of thispatent perispinal administration excludes intrathecal administration,which carries additional risks of infection and hemorrhage. Therefore inthis patent “perispinal” is more exactly defined as “perispinal(extrathecal)”, but for the purposes of brevity shall be designatedthroughout simply as “perispinal”. Perispinal administration leads toenhanced delivery of large molecules to the brain and the head and thestructures therein in a therapeutically effective amount. Theconventional mode of delivery of these molecules for clinicalapplications, i.e. subcutaneous administration in the abdomen, thighs,or arms, does not effectuate delivery across the blood-brain barrier(see Robinson reference 60) which is as efficient as perispinaladministration and is therefore distinguished from the perispinalmethods of administration described in this invention.

Hearing loss occurs in humans in many forms. Hearing is essential to thenormal conduct of one's daily activities and people with impairedhearing have many difficulties. Hearing loss can date from birth; it canbe acquired later in life; or it can be the result of trauma, accident,disease, or a toxic effect of a medication. It can be genetic, either asa solitary disorder or as part of a complex syndrome. Hearing loss isone of the most common chronic neurological impairments, estimated toaffect about 4 percent of those under 45 in the United States, and about29 percent of those 65 years or older.

As defined herein, the auditory apparatus includes the cochlea, theauditory division of the eighth cranial nerve, and the central auditorypathways. Sensorineural hearing loss is one particular category ofhearing loss and is caused by lesions of the cochlea and/or the auditorydivision of the eighth cranial nerve. Prior to this invention, treatmentof this condition was primarily limited to the use of hearing aids.

The pathogenetic mechanism of most forms of hearing loss has yet to befully defined. Hearing loss can be due to conductive problems, which isnot the subject of this patent; central hearing loss due to lesions ofthe central auditory pathway; or sensorineural hearing loss.

Humans react to sounds that are transduced into neurally conductedimpulses through the action of neuroepithelial cells (hair cells) andspiral ganglion cells (neurons) in the inner ear. These impulses aretransmitted along the cochlear division of the eighth cranial nerve intothe brainstem and the central auditory pathways.

Presbycusis, or age-related hearing loss, is a type of sensorineuraldeafness which affects one-third of the population over the age of 75.The exact mechanism of presbycusis is unknown, and has long been thoughtto be multifactorial. Inflammation has not previously been thought to bea significant factor in the pathogenesis of presbycusis. Yet a previousstudy did suggest that genes encoded by the major histocompatibilitycomplex (MHC) had a role in certain hearing disorders. (Bernstein, ActaOtolaryngol 1996 September; 116(5):666-71). The MHC is known to becentral to the immune response and inflammation.

As will be discussed below there is now clinical evidence thatinflammation has a role in the pathogenesis of various types ofsensorineural hearing loss, including presbycusis. This opens up a newavenue of treatment of these disorders utilizing large moleculesdelivered by perispinal administration without direct intrathecalinjection, including biologic TNF inhibitors and other large moleculeswith a molecular weight equal to or greater than 2,000 daltons.

As discussed in the previous patents and patent applications of theinventor, including U.S. Pat. Nos. 6,082,089; 6,537,549, and the othersas enumerated above, including those detailed in section 1 of thisapplication, the methods of the present invention may be utilized totreat sciatica, cervical radiculopathy, fibromyalgia, severe low backpain and/or related pain conditions, including neuropathic pain.

4. DESCRIPTION OF THE PRIOR ART

Pharmacologic chemical substances, compounds and agents having variousorganic structures and metabolic functions which are used for thetreatment of sensorineural hearing loss, and TNF related diseases havebeen disclosed in the prior art. One example is U.S. Pat. No. 5,837,681,entitled “Method For Treating Sensorineural Hearing Loss Using GlialCell Line-Derived Neurotrophic Factor (GDNF) Protein Product”. However,this prior art patent does not teach the use of a TNF antagonistdelivered via the vertebral venous system, as in the present invention,and GDNF has biologic actions which are clearly distinct from those ofthe TNF binding biologics of the present invention.

U.S. Pat. No. 6,043,221 entitled “Method For Preventing And TreatingHearing Loss Using A Neuturin Protein Product” discusses the use of aneurotrophic factor. This prior art patent does not teach the use of aTNF antagonist delivered via the vertebral venous system to treatdisorders of the brain, as in the present invention.

U.S. Pat. No. 5,385,901 entitled “Method Of Treating AbnormalConcentrations of TNF Alpha” discloses a method for the use of TNFantagonists. This prior art patent does not teach the use of a biologicdelivered via the vertebral venous system as described in the presentinvention for the suppression and inhibition of the action of TNF in thehuman body to treat disorders of the brain, as in the present invention.

U.S. Pat. No. 5,434,170 entitled “Method For Treating NeurocognitiveDisorders” discloses the use of thalidomide to treat dementia. Thisprior art patent does not teach the use of etanercept or anotherbiologic delivered via the vertebral venous system as described in thepresent invention to treat disorders of the brain.

U.S. Pat. No. 6,277,969 discloses the use of anti-TNF antibodies fortreatment of various disorders. This prior art patent does not teach theuse of etanercept or another biologic delivered via the vertebral venoussystem as described in the present invention to treat disorders of thebrain.

U.S. Patent application 2004/0258671 by Watkins entitled “Methods forTreating Pain” discloses the use of IL-10 and IL-10 fusion protein andother biologics for treating pain. This patient application does notdisclose the use of these substances to treat disorders of the brain.

U.S. Pat. No. 5,656,272 to LE et. al. discloses the use of TNFinhibitors for treatment of various disorders, including the use ofanti-TNF monoclonal antibodies. This prior art patent does not teach theuse of etanercept or another biologic delivered via the vertebral venoussystem as described in the present invention to treat disorders of thebrain.

U.S. Pat. No. 5,650,396 discloses a method of treating multiplesclerosis (MS) by blocking and inhibiting the action of TNF in apatient. This prior art patent does not teach the use of etanercept oranother biologic delivered via the vertebral venous system as describedin the present invention to treat disorders of the brain.

U.S. Pat. No. 5,605,690 discloses the use of TNF inhibitors fortreatment of various disorders. This prior art patent does not teach theuse of etanercept or another biologic delivered via the vertebral venoussystem as described in the present invention to treat disorders of thebrain.

U.S. patent application US 2003/0148955 to Pluenneke discloses the useof biologic TNF inhibitors, including etanercept, for the treatment ofmedical disorders. However, it does not give an enabling disclosure ofthe use of etanercept for the treatment of disorders of the brainutilizing the vertebral venous system as does the present invention andit does not predate the U.S. Pat. No. 6,015,557 of the present inventorof which this patent application is a continuation-in-part.

U.S. Pat. Nos. 7,115,557, 6,649,589 and 6,635,250 and related patentapplications which have not been granted, to Olmarker and Rydevik, andprevious publications by Olmarker (see References) discuss the use ofTNF inhibitors for the treatment of nerve root injury and relateddisorders. These patents do not teach the use of etanercept or anotherbiologic delivered via the vertebral venous system as described in thepresent invention to treat disorders of the brain, and are not enablingwith respect to etanercept, golimumab, certolizumab pegol, and othermolecules discussed herein.

U.S. Pat. No. 5,863,769 discloses using IL-1 RA for treating variousdiseases. This prior art patent does not teach the use of an interleukinantagonist or other biologic delivered via the vertebral venous systemas described in the present invention to treat disorders of the brain.

U.S. Pat. No. 6,013,253 discloses using interferon and IL-1 RA fortreating multiple sclerosis. This prior art patent does not teach theuse of an interleukin antagonist or other biologic delivered via thevertebral venous system as described in the present invention to treatdisorders of the brain.

U.S. Pat. No. 5,075,222 discloses the use of IL-1 inhibitors fortreatment of various disorders. This prior art patent does not teach theuse of an interleukin antagonist or other biologic delivered via thevertebral venous system as described in the present invention to treatdisorders of the brain.

U.S. Pat. No. 6,159,460 discloses the use of IL-1 inhibitors fortreatment of various disorders. This prior art patent does not teach theuse of an interleukin antagonist or other biologic delivered via thevertebral venous system as described in the present invention to treatdisorders of the brain.

U.S. Pat. No. 6,096,728 discloses the use of IL-1 inhibitors fortreatment of various disorders. This prior art patent does not teach theuse of an interleukin antagonist or other biologic delivered via thevertebral venous system as described in the present invention to treatdisorders of the brain.

U.S. Pat. No. 6,548,527 to Rahman discloses the use of etanercept forthe treatment of immune mediated ear disorders. This prior art patentdoes not teach the use of etanercept or other biologic delivered via thevertebral venous system as described in the present invention to treatdisorders of the brain.

US patent application 20040072885 to Rahman discloses the use ofetanercept for the treatment of immune mediated ear disorders. Thisprior art patent does not teach the use of an etanercept or otherbiologic delivered via the vertebral venous system as described in thepresent invention to treat disorders of the brain.

An article (Rahman M U, Poe D S, Choi H K. Etanercept therapy forimmune-mediated cochleovestibular disorders: preliminary results in apilot study. Otol Neurotol. 2001 September; 22(5):619-24.) disclosed theuse of etanercept by subcutaneous administration for the treatment ofimmune mediated ear disorders. This prior art patent does not teach theuse of etanercept or other biologic delivered via the vertebral venoussystem as described in the present invention to treat disorders of thebrain.

Clemens (reference 57) demonstrated that the internal and externalvertebral venous plexuses freely intercommunicate, and this was alsodemonstrated by Vogelsang (reference 58) with the use of intraosseousspinal venography. But neither Clemens nor Vogelsang discussed the useof the VVS to facilitate delivery of large molecules to the brain, nordid they discuss the use of the VVS for therapeutic purposes.

Groen (reference 50) confirmed the fact that all three divisions of thevertebral venous system (internal and external plexuses, and thebasivertebral veins) freely intercommunicated, and that all divisions ofthis system lacked valves. But Groen did not discuss the use of the VVSto facilitate delivery of large molecules to the brain, nor did hediscuss the use of the VVS for therapeutic purposes.

Two recent articles (Lirk references 54 and 55) discuss an anatomicfinding, disclosing the existence of a gap in a ligamentous barrier tothe epidural space. These articles, however, do not discuss theadministration of large molecules by the perispinal route, or therelevance of this anatomic finding to the delivery of large molecules tothe brain.

Batson in 1940 (reference 47) published information regarding thevertebral venous system. Experimentally he demonstrated a connectionbetween the pelvic venous system and the vertebral venous system, andproposed that this was a route whereby carcinoma originating in thepelvis could metastasize to the spine. His work did not propose the useof the VVS for therapeutic purposes, nor did it discuss or imply thispossibility. His work did not disclose the methods of the presentinvention for delivery of large molecules to the brain.

Ruiz and Gisolf (references 44 and 45) have recently published articlesdiscussing the vertebral venous system and its connections to thecranial venous system. Neither authors discuss the potential use of thissystem as a route of administration of large molecules to the brain.

Retrograde cerebral perfusion has been previously demonstrated todeliver dye to the surface of the brain in pigs after superior venacaval injection (Ye reference 42)) but the authors did not propose theuse of this route to deliver large molecules to the brain.

Several authors (references 44-50) have discussed the anatomy andfunction of the vertebral venous system but none have proposed the useof the vertebral venous system as a route of delivery of large moleculesto the brain, nor have they proposed the methods of the presentinvention.

Two articles by Byrod discussed a mechanism whereby substances appliedepidurally can cross into the endoneurial space (Byrod references 51 and52), but neither article discusses the perispinal use of a largemolecule for delivery to the brain.

Robinson (reference 60) states the prevailing view that systemicadministration of etanercept does not lead to therapeutic concentrationsof etanercept in the brain, because systemically administered etanerceptdoes not cross the BBB.

Markomichelakis (reference 62) in 2005, following the issuance of U.S.Pat. No. 6,428,787 by this inventor which claimed the use of infliximabto treat macular degeneration, described the regression of maculardegeneration following infliximab treatment given systemically. Thisreference did not describe or discuss the use of perispinal infliximab.

Olmarker has filed patent applications regarding the use of anti-TNFmolecules for treatment of spinal disorders, including US20010027175,20010055594, 20030176332, 20050220791, 20010027199, and 20030039651,which have led to U.S. Pat. Nos. 6,635,250, 6,649,589, and 7115557. Noneof these applications or patents are enabling for the use of perispinaletanercept or perispinal golimumab for the applications discussed in thepresent invention.

None of the prior art patents disclose or teach the use of perispinaladministration of large molecules as in the present invention as a wayof delivering large molecules to the brain, the eyes, or the head, inwhich this method of administration provides the patient with a betteropportunity to heal, slows disease progression, treats infection orotherwise improves the patient's health.

None of the prior art patents disclose or teach the use of perispinaladministration of golimumab as in the present invention as a way ofdelivering golimumab to the brain, the eyes, or the head, in which thismethod of administration provides the patient with a better opportunityto heal, slows disease progression, treats infection or otherwiseimproves the patient's health.

In addition the prior art does not contain a description of the methodsof the current invention to deliver molecules smaller than 2,000 daltonsMW to the brain and other structures of the head.

Accordingly, it is an object of the present invention to providegolimumab administered through the perispinal route as a new method ofgolimumab so that the use of golimumab will improve a patient's health.

Another object of the present invention is to provide a method todeliver golimumab across the blood-brain barrier so that it is deliveredto the brain in a therapeutically effective dose and thereby treats adisease or disorder of the brain.

Another object of the present invention is to provide a method todeliver golimumab across the blood-eye barrier so that it is deliveredto the eye in a therapeutically effective dose and thereby treats adisease or disorder of the eye.

Another object of the present invention is to provide a method todeliver golimumab across the blood-eye barrier so that it is deliveredto the retina in a therapeutically effective dose and thereby treats adisease or disorder of the retina.

Another object of the present invention is to provide a method todeliver golimumab across the blood-eye barrier so that it is deliveredto the retina in a therapeutically effective dose and thereby treatsmacular degeneration.

Another object of the present invention is to provide a method todeliver golimumab across the blood-eye barrier so that it is deliveredto the retina in a therapeutically effective dose and thereby treats adisease or disorder of the diabetic retinopathy.

Another object of the present invention is to provide a method todeliver golimumab across the blood-brain barrier so that it is deliveredto the auditory apparatus in a therapeutically effective dose andthereby treats a disease or disorder of the auditory apparatus.

Another object of the present invention is to provide a method todeliver golimumab across the blood-brain barrier so that it is deliveredto the brain in a therapeutically effective dose and thereby treatsdementia.

Another object of the present invention is to provide a method todeliver golimumab across the blood-brain barrier so that it is deliveredto the brain in a therapeutically effective dose and thereby treats abrain tumor.

Another object of the present invention is to provide a method todeliver golimumab across the dural barrier so that it is delivered tothe spine in a therapeutically effective dose and thereby treats amalignant tumor metastatic to the spine.

Another object of the present invention is to provide a method todeliver golimumab across the dural barrier so that it is delivered tothe spinal nerve roots, the spinal cord, the dorsal root ganglia, or thespine in a therapeutically effective dose and thereby treats a spinaldisorder, including sciatica, degenerative disc disease, cervicalradiculopathy, low back pain, or related conditions.

Accordingly, it is an object of the present invention to provide largemolecules administered through the perispinal route as a new method ofuse of such molecules so that the use of these molecules will improve apatient's health.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-brain barrier so that it isdelivered to the brain in a therapeutically effective dose and therebytreats a disease or disorder of the brain.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-eye barrier so that it isdelivered to the eye in a therapeutically effective dose and therebytreats a disease or disorder of the eye.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-eye barrier so that it isdelivered to the retina in a therapeutically effective dose and therebytreats a disease or disorder of the retina.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-eye barrier so that it isdelivered to the retina in a therapeutically effective dose and therebytreats macular degeneration.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-eye barrier so that it isdelivered to the retina in a therapeutically effective dose and therebytreats a disease or disorder of the diabetic retinopathy.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-brain barrier so that it isdelivered to the auditory apparatus in a therapeutically effective doseand thereby treats a disease or disorder of the auditory apparatus.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-brain barrier so that it isdelivered to the brain in a therapeutically effective dose and therebytreats dementia.

Another object of the present invention is to provide a method todeliver a large molecule across the blood-brain barrier so that it isdelivered to the brain in a therapeutically effective dose and therebytreats a brain tumor.

Another object of the present invention is to provide a methods todeliver a molecules with a molecular weight less than 2,000 daltonsacross the blood-brain barrier so that it they are delivered to thebrain, the eye, or the auditory apparatus in a therapeutically effectivedose.

None of the prior art patents or articles disclose or teach the use ofperispinal administration without direct intrathecal injection ofetanercept or other large molecules, as in the present invention, as away of treating a brain, retina, or cranial nerve disorder, in whichsaid large molecule is delivered via the vertebral venous system andprovides the patient with a better opportunity to heal, slows diseaseprogression, improves brain or retinal function or otherwise improvesthe patient's health.

Accordingly, it is an object of the present invention to provide largemolecules administered into the perispinal area, outside of theintrathecal space, via the vertebral venous system, as a new method ofbiologic treatment of neurological conditions of the brain, retina, eyeor auditory apparatus such that the use of these large molecules willresult in improved health.

Another object of the present invention is to provide large moleculesdelivered via the vertebral venous system for providing suppression andinhibition of the action of specific cytokines in a human to treatdisorders of the brain, retina, cranial nerves, spine, spinal cord,spinal nerve roots, dorsal root ganglia or hearing.

Another object of the present invention is to provide a large moleculedelivered via the vertebral venous system so that it is delivered to thebrain, retina, cranial nerves, or auditory apparatus in atherapeutically effective dose and thereby improves disorders of thebrain, retina, cranial nerves, or hearing.

Another object of the present invention is to provide large moleculesthat produce biologic effects in patients with vision loss by inhibitingthe inflammatory cascade in the human body for the immediate, short term(acute conditions) and long term (chronic conditions), such that thesebiologic effects will produce clinical improvement in the patient andwill give the patient a better opportunity to heal, improve vision, slowvision loss, prevent neurological damage, or otherwise improve thepatient's health.

Another object of the present invention to provide a cancerchemotherapeutic agent delivered via the vertebral venous system for thetreatment of a malignant disease of the brain in a human such that theuse of this cancer chemotherapeutic agent results in decreased ordelayed growth of the malignancy.

Another object of the present invention to provide bevacizumab deliveredvia the vertebral venous system for the treatment of a malignant diseaseof the brain in a human such that the use of bevacizumab results indecreased or delayed growth of the malignancy.

Another object of the present invention to provide pegaptanib orranibizumab delivered via the vertebral venous system for the treatmentof a malignant disease of the brain in a human such that the use ofbevacizumab results in decreased or delayed growth of the malignancy.

Another object of the present invention to provide pegaptanib orranibizumab delivered via the vertebral venous system for the treatmentof ocular neovascularization in a human such that the use of pegaptanibor ranibizumab results in improved vision.

Another object of the present invention to provide pegaptanib orranibizumab delivered via perispinal administration for the treatment ofa malignant disease of the brain in a human such that perispinaladministration results in effective delivery of pegaptanib orranibizumab via the vertebral venous system thereby resulting indecreased or delayed growth of the malignancy.

Another object of the present invention to provide pegaptanib orranibizumab delivered via perispinal administration for the treatment ofocular neovascularization in a human such that perispinal administrationresults in effective delivery of pegaptanib or ranibizumab via thevertebral venous system thereby resulting in improved vision.

Another object of the present invention to provide bevacizumab deliveredvia perispinal administration for the treatment of a malignant diseaseof the brain in a human such that perispinal administration results ineffective delivery of bevacizumab via the vertebral venous systemthereby resulting in decreased or delayed growth of the malignancy.

Another object of the present invention to provide a TNF antagonistdelivered via the vertebral venous system for the treatment ofsensorineural hearing loss in a human such that the use of thisantagonist results in improved hearing.

Another object of the present invention to provide a TNF antagonist forthe treatment of sensorineural hearing loss in a human such that the useof this antagonist results in improved hearing without the use of ahearing aid, in a manner that is both safe and effective.

Another object of the present invention to provide a TNF antagonistdelivered via the vertebral venous system for the treatment of visionloss in a human such that the use of this antagonist results in improvedvision without the need for surgery.

Another object of the present invention is to provide novel and improvedroutes of administration for the selected TNF antagonist so that itenters the vertebral venous system in a therapeutically effective amountfor the treatment of macular degeneration in a human such that the useof this antagonist with this method results in improved vision or indelay of disease progression in a manner that is both safe, effective,and economical.

Another object of the present invention is to provide novel and improvedroutes of administration for the selected biologic so that it enters thevertebral venous system in a therapeutically effective amount for thetreatment of a clinical disorder of the brain in a human such that theuse of this biologic with this method results in improved health in amanner that is both safe, effective, and economical.

5. SUMMARY OF THE INVENTION

The present invention provides specific methods for delivering golimumabto a mammal utilizing perispinal administration without directintrathecal injection. For the purposes of this patent “perispinal” isto be considered as referring to “perispinal extrathecal”; thereforedirect intrathecal administration is excluded from the methodsdiscussed.

The term “treatment” as used herein in the context of treating acondition, refers generally to the treatment and therapy, whether ahuman or an animal, in which some desired therapeutic effect isachieved, for example the inhibition of the progression of the conditionor illness, and includes the reduction in the rate of progress, a haltin the progression of an illness, amelioration of the adverse condition,and cure of the condition. Treatment as a prophylactic measure, as wellas combination treatments and therapies are also included.

As used herein, “therapeutically effective” refers to the material oramount of material which is effective to prevent, alleviate, orameliorate one or more symptoms or signs of a disease or medicalcondition, produce clinical improvement, delay clinical deterioration,and/or prolong survival of the subject being treated.

As used herein, “subject” refers to animals, including mammals, such ashuman beings, domesticated animals, and animals of commercial value.

As used herein, the term “biologic” is defined as a drug which isderived or prepared from the DNA of a living organism, which has arelatively large molecular weight and a high structural complexity ascompared with biologically active substances which are produced bychemical synthesis. The living sources from which biologics may beobtained include humans, other animals, and microorganisms. The drug maybe produced by recombinant means, or may be extracted and purifieddirectly from the living source.

As used herein, “perispinal administration without direct intrathecalinjection” refers to administration adjacent to the spine, but outsideof the intrathecal space (extrathecal), wherein the injection needle orcatheter does not penetrate the dural barrier. Administration thereforeis not directly into the cerebrospinal fluid.

Non-brain capillaries are made up of endothelial cells which areseparated by small gaps that allow chemicals in solution to pass intothe blood stream, where they can be transported thoughout the body. Innon-brain capillaries, compounds having molecular weights greater than25,000 Daltons can undergo transport. In contrast, endothelial cells inbrain capillaries are more tightly packed, due to the existence ofzonula occludentes (tight junctions) between them, thereby blocking thepassage of most molecules. The blood-brain barrier blocks most moleculesexcept those that cross cell membranes by means of lipid solubility(such as, for example, oxygen, carbon dioxide, and ethanol) and thosewhich are allowed in by specific transport systems (such as, forexample, sugars, amino acids, purines, nucleosides and organic acids).Generally, it is accepted that substances having a molecular weightgreater than 500 daltons cannot cross the blood-brain barrier, whereassubstances having a molecular weight less than 500 daltons can cross theblood-brain barrier.

Because they do not effectively cross the blood-brain barrier, biologicshaving a molecular weight greater than 500 are not effective whenadministered systemically. For example, etanercept has a molecularweight of 150,000 Daltons, and is not effective for treating conditionsof the brain, eye, spinal chord, and cranial nerves. Thus, utilizationof the VVS is particularly useful for the administration of highmolecular weight biologics such as bevacizumab or etanercept, fordelivery to the brain, retina, eye, cranial nerves, spine and spinalcord, thereby enabling the treatment of a wide range of previouslyintractable disorders of the brain, the retina, and the nervous system,including those which are inflammatory, malignant, infectious,autoimmune, vascular, and degenerative.

In addition the methods of the present invention may be used to delivermolecules with a MW less than 2,000 daltons to the brain and otherstructures of the head more efficiently than if delivered systemically,and these methods utilizing these smaller molecules are also to beconsidered a part of this invention.

Perispinal administration involves anatomically localized deliveryperformed so as to place golimumab directly in the vicinity of thespine, and thereby facilitate delivery of golimumab to the brain, theeye, the retina, the auditory apparatus, the cranial nerves, the spinalnerve roots, the dorsal root ganglia, the spinal cord or the head.Perispinal administration includes, but is not limited to, the followingtypes of administration: parenteral; subcutaneous; intramuscular; andinterspinous; and specifically includes the use of interspinousinjection carried through the skin in the midline of the neck or back,directly overlying the spine, so that the large molecule is deliveredinto the interspinous space. Perispinal administration leads to enhanceddelivery of golimumab to the brain, the eye, the retina, the auditoryapparatus, the spine and contiguous structures, and the cranial nervesor the head in a therapeutically effective amount, via the vertebralvenous system. Delivery of a large molecule to the brain utilizing themethods of the present invention includes the use of the vertebralvenous system to deliver the large molecule to the brain via retrogradevenous flow. Physical positioning may also be used to enhance deliveryvia this route.

All of the large molecules available for therapeutic use are approvedfor systemic administration, either by subcutaneous (SC) or intravenous(IV) administration. None have been approved for perispinal orinterspinous administration.

This patent application describes novel methods of administration oflarge molecules, utilizing perispinal administration, which results inimproved efficiency (decreased dose for equivalent therapeutic effect)and/or increased effectiveness (increased therapeutic effect forequivalent therapeutic dose) compared with systemic administration.

This invention is distinguished from the prior art in a variety of ways,including the use and description of novel and useful new uses, methodsof use, and concepts involving large molecules, including:

-   -   1. Novel uses of perispinal administration to enhance delivery        of golimumab and other large molecules to the brain, the eye,        the retina, the auditory apparatus, the cranial nerves or the        head; and    -   2. Novel methods of use of large molecules; and    -   3. Novel concepts, including:        -   a. Perispinal (extrathecal) administration distinguished            from systemic forms of administration and intrathecal            administration;        -   b. The use of the vertebral venous system to deliver            golimumab and other large molecules to the brain, the eye,            the retina, the auditory apparatus, the cranial nerves, the            spinal nerve roots, the dorsal root ganglia, the spinal cord            or the head;        -   c. The use of physical maneuvers to facilitate delivery of            golimumab to the brain, the eye, the retina, the auditory            apparatus, the cranial nerves or the head;        -   d. The use of physical positioning to influence the            direction of venous flow within the vertebral venous system            and thereby deliver therapeutic molecules to the brain, the            eye, the retina, the auditory apparatus, the cranial nerves            or the head;        -   e. The use of retrograde venous perfusion to deliver            therapeutic molecules to the brain, the eye, the retina, the            auditory apparatus, the cranial nerves or the head;        -   f. The use of retrograde venous perfusion via the vertebral            venous system to facilitate delivery of therapeutic            molecules to the brain, the eye, the retina, the auditory            apparatus, the cranial nerves or the head;        -   g. The use of the vertebral venous system as a “back door”            to facilitate delivery of therapeutic molecules to the            brain, the eye, the retina, the auditory apparatus, the            cranial nerves or the head;        -   h. The use of perispinal administration to introduce a large            molecule into the vertebral venous system;        -   i. The use of perispinal administration to efficiently            deliver large molecules to the brain, the eye, the retina,            the auditory apparatus, the cranial nerves, the spinal nerve            roots, the dorsal root ganglia, the spinal cord or the head.

The same methods described for golimumab of this invention also apply toother large molecules, such as etanercept, certolizumab pegol, IL-1Trap, Kineret®, bevacizumab, pegaptanib, ranibizumab, rituximab,Zevalin®, Mylotarg®, Campath®, HumaSpect®, abatacept, cetuximab,panitumumab, pegfilgrastim, filgrastim, erythropoietin, Aranesp®,trastuzumab, Pegasys®, Intron A®, PEG-Intron®, Infergen®, Avonex®,Rebif®, Betaseron®, Actimmune®, Ontak®, Simulect®, Zenapax®, Genkaxin®,recombinant human growth hormone, reteplase, alteplase, tPA (tissueplasminogen activator), urokinase plasminogen activator, streptokinase,urokinase, or immune globulin), and smaller molecules, such as Tarceva®,all of which maybe given by perispinal administration, and whose use, byperispinal administration without direct intrathecal injection,constitute part of this invention.

6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The use of perispinal administration of cytokine antagonists to treatneurological disorders is discussed in US patent application 20030049256of this inventor. The use of perispinal administration without directintrathecal injection and the vertebral venous system to deliver largemolecules to the brain, the eye, and the auditory apparatus arediscussed in the following provisional patent applications:

-   60/585,735 filed Jul. 6, 2004;-   60/659,414 filed Mar. 9, 2005;-   60/662,744 filed Mar. 17, 2005;-   and 60/669,022, filed Apr. 7, 2005,

This is a continuation-in-part of U.S. patent application Ser. No.11/016,047, filed Dec. 18, 2004, entitled “Methods of use of etanerceptto improve human cognitive function”, which is a continuation-in-part ofU.S. Patent Application 20030049256, also known as U.S. patentapplication Ser. No. 10/269,745, entitled “Cytokine antagonists forneurological and neuropsychiatric disorders”, filed Oct. 9, 2002, nowU.S. Pat. No. 6,982,089, which is a continuation-in-part of Ser. No.10/236,097, filed on Sep. 6, 2002, now abandoned, which is acontinuation-in-part of application Ser. No. 09/841,844, filed on Apr.25, 2001, now U.S. Pat. No. 6,537,549, which is a continuation-in-partof application Ser. No. 09/826,976, filed on Apr. 5, 2001, now U.S. Pat.No. 6,419,944, which is a continuation-in-part of application Ser. No.09/563,651, filed on May 2, 2000, which is a continuation-in-part ofapplication Ser. No. 09/476,643, filed on Dec. 31, 1999, now U.S. Pat.No. 6,177,077, which is a continuation-in-part of application Ser. No.09/275,070, filed on Mar. 23, 1999, now U.S. Pat. No. 6,015,557, whichis a continuation-in-part of application Ser. No. 09/256,388, filed onFeb. 24, 1999, now abandoned. This application is also related toprovisional U.S. patent application 60/662,744 entitled “Methods of Useof the Vertebral Venous System to Deliver Biologics to the CNS” filedMar. 16, 2005. The use of perispinal administration of cytokineantagonists to treat neurological disorders is discussed in US patentapplication 20030049256 of this inventor. The use of perispinaladministration without direct intrathecal injection and the vertebralvenous system to deliver large molecules to the brain, the eye, and theauditory apparatus are discussed in provisional patent applications60/585,735 filed Jul. 6, 2004; 60/659,414 filed Mar. 9, 2005; 60/662,744filed Mar. 17, 2005; and 60/669,022, filed Apr. 7, 2005. In additionthis provisional patent application is related to Atty. Docket No.“Tobinick 3.0-027 (Prov)” U.S. provisional patent application entitled“Methods to facilitate transmission of golimumab and other therapeuticmolecules across the blood-brain-barrier” filed with the USPTO on Nov.18, 2005.

All of the above patents and patent applications enumerated in the abovethree paragraphs are incorporated by reference in their entirety herein.

Perispinal administration of a molecule when compared to systemicadministration, carries with it one or more of the following advantagesfor the present invention:

-   -   1) greatly improved efficacy due to improved delivery of the        therapeutic molecule to the brain, the eye, the retina, the        auditory apparatus, the cranial nerves, the spinal nerve roots,        the dorsal root ganglia, the spinal cord or the head via the        vertebral venous system (VVS).    -   2) greater efficacy due to the achievement of higher local        concentration in the interspinous space, leading to improved        delivery to the VVS and the brain, the eye, the retina, the        auditory apparatus, the cranial nerves, the spinal nerve roots,        the dorsal root ganglia, the spinal cord or the head.    -   3) greater efficacy due to the ability of the administered        therapeutic molecule to reach the brain, the eye, the retina,        the auditory apparatus, the cranial nerves, the spinal nerve        roots, the dorsal root ganglia, the spinal cord or the head        without degradation caused by hepatic or systemic circulation;    -   4) more rapid onset of action;    -   5) longer duration of action; and    -   6) Potentially fewer side effects, due to lower required dosage.

These advantages apply to both large molecules, such as monoclonalantibodies, which typically have a MW of more than 100,000 daltons, andto smaller molecules, many of which, even though they have a MW lessthan 2,000 daltons, have difficulty traversing the BBB. Even smallermolecules, those with a MW less than 500 daltons, which often can crossthe BBB, will achieve a greater therapeutic concentration in brain oreye tissue if administered by perispinal delivery without directintrathecal injection, especially if immediately following injection thepostural adjustments are made to direct the head downward with the bodyin a Trendelenburg position, thereby facilitating retrograde venousperfusion via the intracranial anastomoses of the vertebral venoussystem. The blood-eye barrier, for the purposes of this patent, will betraversed by the methods of the present invention in a manner equivalentto the manner in which these molecules cross the blood-brain barrier.The blood-nerve barrier protecting the spinal nerve roots and the spinalcord, consisting in large part of the barrier formed by the dura mater,will also be traversed in a manner utilizing the methods of the presentinvention i.e. by carriage in the vertebral venous system, etc.

The inventor has extensive clinical experience utilizing perispinalinjection of etanercept for the treatment of disc-related pain andradiculopathy, including low back pain, neck pain, lumbar radiculopathy(sciatica), cervical radiculopathy, pain associated with annular tear ofthe intervertebral disc, and pain associated with degenerative discdisease (see Tobinick reference 63) (Tobinick, E. and S. Davoodifar,Efficacy of etanercept delivered by perispinal administration forchronic back and/or neck disc-related pain: a study of clinicalobservations in 143 patients. Curr Med Res Opin, 2004. 20(7): p.1075-85). In this article the inventor reported the results ofperispinal etanercept treatment for 143 patients, including those withdisc bulge, protrusion, extrusion or herniation; lumbar and cervicalradiculopathy; degenerative disc disease; central spinal stenosis;spondylolisthesis; back pain, neck pain, or sciatica; and annular tearof the intervertebral disc. The 143 patients had a mean duration of painof 9.8 years. After a mean of 2.3 doses of perispinal etanercept themean VAS intensity of pain, sensory disturbance, and weakness wassignificantly reduced at 20 min., 1 day, 1 week, 2 weeks, and 1 month.In a previous publication (Tobinick, E. L. and S. Britschgi-Davoodifar,Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly,2003. 133(11-12): p. 170-7) the inventor documented clinical improvementfollowing perispinal etanercept in a cohort of 20 patients with thefollowing diagnoses: acute lumbar radiculopathy; chronic cervical andlumbar discogenic pain; subacute lumbar radiculopathy; chronicdiscogenic pain and failed back surgery syndrome; chronic low back painand sciatica; chronic, treatment-resistant discogenic pain. Rapid,substantial, and sustained clinical pain reduction and improvement infunctional disability was documented in this group of patients for amean of 230 days. At the time that these articles were published theinventor was not aware of the fact that the vertebral venous systemdrains the perispinal area, including both the deeper interspinous spacesuperficial to the ligamentum flavum and the subcutaneous perispinalspace which overlies the spinous processes and the deeper interspinousspace. It is a method of the present invention to introduce largemolecules into this area (the perispinal area) to enable them to draininto the vertebral venous system and thereby cross the blood-nervebarrier and produce therapeutic benefit for treating the spinalconditions enumerated in this paragraph. This may be accomplished byperispinal injection of these molecules, which leads to entry of thelarge molecules into the vertebral venous system, and then delivery ofthese molecules, by retrograde venous flow due to lack of venous valvesin the VVS, to the spinal nerve roots, the dorsal root ganglia, and thespinal cord. In the case of etanercept and golimumab, for example, thisresults in neutralization of excess TNF and clinical improvement inpatients suffering from a variety of spinal ailments, includingspecifically those enumerated in this paragraph. The dosage needed toaccomplish this is outlined in the above articles (references 63 and 64)and elsewhere in this patent application with respect to etanercept. Forgolimumab, the dosage used will vary between 10 and 100 mg, including adosage of 25 mg or 50 mg given as a perispinal extrathecal injection.

The inventor has successful clinical experience with perispinaladministration of etanercept, a large molecule (MW 149,000 daltons) forthe treatment of Alzheimer's Disease (AD) (see experimental resultsinfra) which illustrates the clinical efficacy of this method ofdelivery of large molecules for the treatment of brain disorders, and,specifically, the ability of this delivery method to enable etanerceptto cross the BBB and effectively treat AD. It should be noted that aprevious clinical trial utilizing etanercept (reference 61) deliveredsystemically (by subcutaneous administration remote from the spine)failed to show efficacy, thereby providing prima facie evidence of thesuperiority of perispinal administration to deliver etanercept to thebrain, when a comparison of the failed trial results to the successfulexperimental results obtained utilizing perispinal administration ofetanercept, detailed infra, is made. The methods described hereininvolve the use of perispinal administration to effectively deliverlarge molecules to the brain, the eye, the retina, the auditoryapparatus, the cranial nerves or the head, for therapeutic use in humansand other mammals.

The VVS consists of an interconnected and richly anastomosed system ofveins which run along the entire length of the vertebral canal. Thevertebral venous plexus, for descriptive purposes, has been separatedinto three intercommunicating divisions: the internal vertebral venousplexuses (anterior and posterior) lying within the spinal canal, butexternal to the dura; the external vertebral venous plexuses (anteriorand posterior) which surround the vertebral column; and thebasivertebral veins which run horizontally within the vertebrae (seeFIG. 1, drawn by Frank Netter, MD, which follows the text portion ofthis patent application and is included as an integral part of theapplication). Both the internal and external vertebral venous plexuscourse longitudinally along the entire length of the spine, from thesacrum to the cranial vault. Utilizing corrosion casting and injectionsof Araldite, Clemens demonstrated that the internal and externalvertebral venous plexuses freely intercommunicate, and this was alsodemonstrated by Vogelsang with the use of intraosseous spinalvenography. Groen and his colleagues with an improved Araldite injectiontechnique which utilized thrombolytics, confirmed the fact that allthree divisions of the vertebral venous system (internal and externalplexuses, and the basivertebral veins) freely intercommunicated, andthat all divisions of this system lacked valves. The internal vertebralvenous plexus communicates with the intraspinal and radicular veins andfreely communicates with the external vertebral venous plexus via theintervertebral veins (see references 44-50). In addition, the VVScommunicates with the azygous veins, and has other connections to thecaval venous system, but not efficiently. Therefore a conventionalintravenous injection in the antecubital fossa, for example, or into oneof the large veins of the forearm, which delivers a solution containinga given therapeutic molecule into the caval venous system, does notefficiently deliver the same therapeutic molecule to the VVS. Likewise,delivery of a solution containing a given therapeutic molecule byperispinal administration will not result in efficient delivery of thegiven therapeutic molecule into the caval venous system, but will resultin efficient delivery into the VVS. The caval venous system and the VVSare separate and largely independent (see reference 59), although theyare interconnected, although not in an efficient manner. To phrase thesame thoughts in a different way, it would be accurate to say thatperispinal administration of a large molecule will result in efficientdelivery of the large molecule to the VVS, with only a small amount ofdelivery of the large molecule into the caval venous system. Delivery ofthe same large molecule by intravenous infusion into an arm vein, forexample, will deliver the large molecule to the caval venous system,expose the large molecule to dilution throughout the body, and fail todeliver the large molecule to the brain, the eye, the retina, theauditory apparatus, the cranial nerves or the head.

A specific anatomic route, by which a large molecule delivered byperispinal administration reaches the brain, has been defined by theinventor (see FIG. 2). This route is as follows. A large molecule isdelivered to the interspinous space in proximity to the ligamentumflavum by percutaneous injection through the skin by midlineinterspinous needle injection. Large molecules delivered to theinterspinous space in this way (being the anatomic region in the midlineof the back, in-between two adjacent spinous processes) are deliveredinto the VVS because the VVS serves to provide venous drainage to theinterspinous space and subcutaneous space which is posterior to thespine (see Batson references 48 and 49 for a discussion of the VVS,which, however, does not discuss the therapeutic potential of the VVS).Solutions injected into this area, therefore, will be preferentiallyabsorbed into the VVS rather than into the caval venous system. Inaddition, a more direct route to the epidural space is also possible forsolutions injected into the interspinous space, by travel throughmidline defects in the ligamentum flavum. Midline defects in theligamentum flavum are common, particularly in the cervical region. Whenpresent the midline ligamentum flavum defect provides a direct route ofaccess for large molecules to the epidural space. Within the epiduralspace lies a richly interconnected venous plexus (which is part of theVVS), which is valveless and which is capable of transporting largemolecules rapidly in the cephalad or caudad directions (see Batsonreferences 48 and 49). Flow within the VVS is bidirectional. Thereforelarge molecules injected into the interspinous space drain directly intothe VVS and thereby gain direct access to the brain, if the patient ispositioned properly immediately following injection so that gravity isused to direct flow via the VVS toward the brain. This is possiblebecause the flow within the VVS can be bidirectional; therefore theseveins serve not only to drain blood from the brain, but also to delivervenous blood to the brain, in retrograde fashion, via the venousconnections of the VVS with the intracranial venous system, includingthe dural sinuses. This retrograde flow is made possible by the lack ofvenous valves in the VVS. Retrograde venous delivery of large moleculesto the brain is a method of the present invention and a discovery of theinventor. The author has detailed much of his current thinking regardingthe vertebral venous system and its connection with the cerebral venoussystem in a recently published article entitled “The CerebrospinalVenous System: Anatomy, Physiology, and Clinical Implications” publishedin Medscape General Medicine in February 2006 (MedGenMed. 2006 Feb. 22;8(1):53.) This article is incorporated in its entirety in this patentapplication by reference.

The VVS can be used to deliver large biologic therapeutic agents (i.e.,biologics having a molecular weight greater than 600 Daltons, preferablygreater than 2000 Daltons) utilizing retrograde venous flow from the VVSinto the cranial venous sinuses and the intracranial venous system fordelivery to the cerebral cortex, eye, retina, spine, cerebellum,brainstem, eighth cranial nerve, cochlea, inner ear, cerebrospinalfluid, spine, spinal cord, dorsal root ganglion, spinal nerve roots,reproductive organs and spinal nerve roots of a subject. Exemplarypharmaceutically acceptable therapeutic agents may include pharmacologicagents, cytokine antagonists and growth factors which can affectneuronal function or the immune response impacting neuronal function,including, but not limited to, for example, golimumab, CDP 870, andetanercept.

Retrograde venous delivery of large molecules to the brain isfacilitated by body positioning after interspinous injection. Forexample, if following cervical interspinous injection the patient isplaced in the head down trendelenburg position then the inventor hasdiscovered that this will lead to effective delivery of the largemolecule to the brain, via retrograde flow in the VVS into the cranialvenous system.

BRIEF DESCRIPTION OF THE FIGURES ACCOMPANYING THE TEXT PORTION OF THISAPPLICATION

FIG. 1 is a scan of a photograph, taken at the National Library ofMedicine, of plate 5 drawn by Breschet and published in 1828 (reference56), depicting the cranial and vertebral venous systems, theiranastomoses, and their anatomic characteristics, especially inrelationship to other anatomic features of the brain and spine.

FIG. 2 is a diagram depicting perispinal administration, in accordancewith the present invention.

FIG. 3 are drawings by Frank Netter, MD depicting three differentanatomic views of the vertebral venous system (VVS) and its anatomicrelationship to the interspinous space and other anatomic elements ofthe spine.

FIG. 1 depicts the anastomoses between the cranial and vertebral venoussystems. Perispinal administration for delivery to the brain and otherstructures of the head is preferably performed by a percutaneousinjection into an interspinous space in the posterior cervical area (12in FIG. 2). As shown in more detail in FIG. 2, hollow needle (26)containing etanercept (or other therapeutic molecule of this invention)in solution (30) is injected through the skin 18 into the interspinousspace 24. If the needle were carried further it could penetrate theligamentum flavum (22), delivering the therapeutic molecule into theepidural space (28) surrounding the spinal cord (36), although in mostiterations of this invention the ligamentum flavum is not penetrated bythe needle, and the therapeutic molecule is deposited into theinterspinous space more superficially, without penetration of theligamentum flavum. The therapeutic molecule in the interspinous spacedrains into the vertebral venous system, and is then carried to thebrain, the eye, the auditory apparatus, and other structures of thehead. (34) is a spinal nerve root.

The interspinous space (24) is defined as the space between two adjacentspinous processes (20). FIG. 3 shows the interspinous space (24) havingveins (38) (FIG. 3) which collect the therapeutic molecule, in this caseetanercept, which reaches the interspinous space after percutaneousinterspinous injection and which veins drain said therapeutic moleculeinto the VVS, so that, utilizing the physical maneuvers of the presentinvention, the therapeutic molecule is transported via retrograde venousflow into the intracranial veins via the anastomoses depicted in FIG. 1,and thence to the brain, the eye, the auditory apparatus, or otherstructures of the head.

The inventor is using the vertebral venous system in a non-obvious wayfor the inventions disclosed herein. For a venous system is routinelyconceptualized as a system that drains blood from a target area ororgan. For example the venous system which drains the kidneys is widelyacknowledged to be a vascular system that drains blood from the kidneys,not as a way of delivering a therapeutic molecule to the kidneys.Likewise the venous system of the brain is widely medically recognizedas a system which functions to drain blood from the brain. It would becounter-intuitive to propose using the VVS to deliver a therapeuticmolecule to the brain, by conventional thinking. Likewise the use of thevertebral venous system to achieve delivery of therapeutic compounds tothe brain is not obvious, because conventional thinking is that thisvenous system functions to drain venous blood away from these anatomicsites. Therefore the inventions of consideration here are in this waycounter-intuitive, because they rely on the vertebral venous system todeliver therapeutic molecules (including specifically large molecules)to the brain, the eye, the retina, the auditory apparatus, the cranialnerves or the head. This delivery is accomplished by retrograde venousflow (opposite from the usual direction), which is made possible by thelack of valves in this venous system, and by the proper use of gravityand positioning of the patient so that venous flow in the desireddirection is accomplished. The rich connections between the cranialvenous system and the vertebral venous system were beautifully depictedin 1828 by Breschet (reference 56), but this anatomic route remainslargely unrecognized by the medical community till the present time.

Correct positioning of the patient so as to facilitate retrograde flowin the desired direction is utilized as part of the present invention toachieve improved delivery of golimumab and other large molecules to thebrain, the eye, the retina, the auditory apparatus, the cranial nervesor the head from its injection point. Since the target is delivery ofthe large molecule to the brain, the eye, the retina, the auditoryapparatus, the cranial nerves or the head, positioning followingdelivery utilizing head-down trendelenburg positioning, assists indelivering the large molecule to the target. In most cases, for deliveryof a large molecule to the brain, the eye, the retina, the auditoryapparatus, the cranial nerves or the head, interspinous injection ispeformed overlying the posterior aspect of the cervical spine, in theinterspinous region between the C4 and C8 spinal processes, followed byplacement of the patient in the head-down trendelenburg position,usually in the prone position, if possible, since the large molecule isdelivered, as described, to an area dorsal to the spine.

Batson's plexus may be used to introduce a variety of therapeuticmolecules to the brain, retina, cranial nerves, and head via retrogradevenous flow from Batson's plexus into the cranial venous sinuses and theintracranial venous system. This method bypasses the well known barrierwhich prevents large molecules introduced into the systemic circulationfrom reaching the brain (the BBB). The BBB prevents molecules largerthan approximately 600 daltons from entering the brain via the systemiccirculation. Virtually all biopharmaceuticals are larger than this. Forexample, etanercept has a molecular weight of 149,000 daltons, andinsulin has a MW of 5,000 (compared with water which has a MW of 18).This method is particularly useful, therefore, for the administration ofbiologics, such as etanercept, erythropoietin, GM-CSF, ranibizumab,etc., whose size when delivered systemically prevents their efficientpassage into the brain, retina, eye, and cranial nerves, but whosepotency, because of their biologic origin, is extremely high. Effectivedelivery of these molecules to the brain, the retina, the eye, and thecranial nerves using the methods of the present invention therebyenables the treatment of a wide range of previously intractabledisorders of the brain, the retina, and the nervous system, includingthose which are inflammatory; malignant; infectious; autoimmune;vascular; and degenerative.

The vertebral venous system is both anatomically and physiologicallydistinct from the venous system which drains the abdomen and thorax,which has been designated by others as the intracavitary venous system,with the vertebral venous system designated as the extracavitary venoussystem. Other nomenclature for the VVS also comes to mind, such as thevalveless venous system, or the bi-directional venous system, but theyare perhaps less suitable than the VVS. The VVS and the intracavitaryvenous system also share anastomoses, as has been discussed at length byBatson. Batson has also described the retrograde flow possible with theVVS, but has not proposed the possible use of the VVS as a route todeliver therapeutic compounds, nor has anyone else. Again, thisretrograde route of delivery is uniquely possible utilizing the VVSbecause of the lack of venous valves.

Use of the vertebral venous system as a route to deliver golimumab tothe retina, eye or optic nerve via retrograde venous flow is a novel newdelivery method for treating disorders of the brain, retina, eye oroptic nerve.

This method allows the treatment of inflammatory or degenerativedisorders of the retina and/or optic nerve, such as maculardegeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa,which involve excessive levels of TNF or which are mediated by VEGF.Excess TNF appears to have a direct deleterious effect on vision, andetanercept, delivered via the vertebral venous system, appears to havethe ability to ameliorate this adverse effect. Perispinal administrationof these biologics enables the biologic to reach the internal contentsof the eye, including the choroidal vasculature and the retina, intherapeutic amounts, via retrograde flow within the cranio-vertebralvenous system.

The methods of the present invention include the perispinaladministration of the biologics of consideration herein (listed below),which can be accomplished in various ways, including transcutaneousinterspinous injection, or catheter delivery into the epidural orinterspinous space, which results in the biologics being delivered intothe vertebral venous system and thence into the brain, retina, cranialnerves, and auditory apparatus in a therapeutic amount.

As defined herein, the auditory apparatus includes the cochlea, theauditory division of the eighth cranial nerve, and the central auditorypathways. Sensorineural hearing loss is one particular category ofhearing loss and is caused by lesions of the cochlea and/or the auditorydivision of the eighth cranial nerve. Prior to this invention, treatmentof this condition was primarily limited to the use of hearing aids.

Midline interspinous administration of etanercept has been demonstrated(see below) to produce improvement in hearing to individuals withcertain forms of non-conductive hearing loss. In addition topercutaneous injection into the interspinous space, etanercept may alsobe delivered to the interspinous or epidural space by implantablecatheter, with the catheter reservoir placed remotely, such as in theabdominal area.

The inventor first described improvement in hearing in a 73 y.o. patientafter perispinal administration of etanercept for the treatment ofsciatica in U.S. Pat. No. 6,423,321. The anatomic route which enablesthe efficient delivery of perispinal etanercept to the brain isidentified by the inventor, and physical maneuvers to facilitate thisprocess are described herein. For the purposes of this patent perispinaletanercept is distinguished from the use of etanercept delivered bysubcutaneous administration at anatomic sites, such as the abdomen,thighs, and arms, which are remote from the spine.

Bevacizumab (Avastin™, Genentech) is a recombinant humanized monoclonalIgG1 antibody that binds to and inhibits the biologic activity of humanvascular endothelial growth factor (VEGF) and which may be useful forthe treatment of retinal disorders which involve neovascularization.Bevacizumab has a molecular weight of 149,000 daltons and is thereforetoo large to readily cross the blood-brain barrier if administeredsystemically. Administration of bevacizumab via the vertebral venoussystem bypasses the blood-brain barrier and allows a therapeutic dose ofbevacizumab to reach the retina, therefore enabling the treatment ofretinal disorders which involve neovascularization, including maculardegeneration and diabetic retinopathy. For this purpose bevacizumab maybe administered via perispinal administration, thereby providing accessof this monoclonal antibody to the VVS and therefore to the retina.

Pegaptanib and ranibizumab are two biologics which are antagonists ofhuman vascular endothelial growth factor (VEGF) and which may be usefulfor the treatment of retinal disorders which involve neovascularization.Pegaptanib is a VEGF-neutralizing oligonucleotide aptamer which bindsand sequesters VEGF, thereby preventing VEGF receptor activation.Ranibizumab is a recombinant humanized monoclonal antibody fragment withspecificity for VEGF. Both pegaptanib and ranibizumab are too large toreadily cross the blood-brain barrier or the blood-ocular barrier ifadministered systemically. They have both shown some efficacy intreating ocular neovasculariztion when administered by injection intothe eye by the intravitreal route. Administration of these agents viathe vertebral venous system bypasses the blood-brain barrier and theblood-ocular barrier and allows a therapeutic dose to reach the retina,therefore enabling the treatment of retinal disorders which involveneovascularization, including macular degeneration and diabeticretinopathy, without the necessity for intravitreal injection. For thispurpose pegaptanib and ranibizumab may be administered via perispinaladministration, thereby providing access of biologics to the VVS andtherefore to the retina, the choroidal vessels, and the eye withoutrequiring intravitreal injection. Additionally perispinal injection ofthese two biologics will enable effective delivery of these agents tothe brain, thereby allowing the use of these agents for brain tumors andother clinical disorders which will respond positively to modulation ofVEGF.

Perispinal administration for delivery of neuroactive molecules otherthan etanercept, including biologics, cytokines, anti-cytokines,hormones or drugs via the vertebral venous system, in a manner similarto that outlined herein, may be performed. The neuroactive compoundsinclude the individual interleukins IL-1, IL-2, IL-4, IL-6, IL-10, orIL-13; interleukin 1 antagonists, such as IL-1 RA (Kineret®, Amgen) andIL-1 Trap; fusion proteins, such as IL-10 fusion protein or etanercept(Enbrel®, Immunex); other TNF antagonists, including certolizumab pegol,soluble TNF receptor type I or pegylated soluble TNF receptor type 1;human growth hormone and related biologics (recombinant human growthhormone, Humatrope® (somatropin) Eli Lilly & Co., Nutropin®/Nutropin AQ®(somatropin), Geref® (sermorelin) Serono, and Protropin® (somatrem)Genentech)); BDNF; erythropoietin (Epogen® (epoetin alpha) Amgen,Procrit® (epoetin alpha) Johnson & Johnson); G-CSF (Neupogen®(filgrastim), Amgen); GM-CSF; Intron® A (interferon alfa-2b)Schering-Plough; Avonex® (interferon beta-1a) Biogen; Alefacept(LFA-3/IgG1 human fusion protein, Amevive® Biogen); Epidermal growthfactor; anti-EGF (ABX-EGF, Abgenix); transforming growth factor-beta 1(TGF-beta 1); NGF; bevacizumab (Avastin™, Genentech); Copaxone®(glatiramer acetate), pegaptanib or ranibizumab as discussed above; orother compounds with CNS, immune, or vascular therapeutic activity.

In particular this invention involves the perispinal administration ofgolimumab. Golimumab is currently in clinical development byCentocor/Schering-Plough for treatment of rheumatoid arthritis, withpotential applications for uveitis, asthma, and Crohn's Disease. It maybe described as a immunoglobulin G1, anti-(human tumor necrosis factorα) (human monoclonal CNTO 148 γ1-chain), disulfide with human monoclonalCNTO 148 κ-chain), dimer, and has CAS Registry number 476181-74-5. It isa fully human anti-TNF monoclonal antibody.

This invention involves the use of the above molecules delivered via thevertebral venous system either alone, as monotherapy, or combined withthe use of other therapeutics delivered orally or otherwise fortreatment of the conditions of consideration herein. For example, theinventor has demonstrated improvement in cognitive function inindividuals with MCI or AD treated with either perispinal etanerceptalone, or perispinal etanercept in combination with memantine and/or acholinesterase inhibitor (chosen from the group of donepezil,rivastigmine or galantamine).

A biologic delivered via the vertebral venous system to the retina andthe eye after perispinal administration is specifically included as aninvention of the current patent.

The methods of the present invention are also distinguished from directintrathecal administration of large molecules.

The large molecules of the current invention include, but are notlimited to, the following:

-   -   a. Colony-stimulating factors (including G-CSF, such as        filgrastim, pegfilgrastim, and lenograstim; GM-CSF, including,        but not limited to sargramostim and molgramostim; Erythroid        growth factors, including, but not limited to: recombinant        erythropoietin (EPO): epoetin alpha, darbepoetin alpha; and        others.    -   b. TNF antagonists with a molecular weight greater than or equal        to 2,000 daltons, including, but not limited to: golimumab,        etanercept, infliximab, certolizumab (CDP 870, Cimzia®), CDP        571, onercept, pegylated soluble TNF receptor type I, soluble        TNF receptor type I.    -   c. Interferons, interferon antagonists, and interferon fusion        proteins, including, but not limited to: IL-1 Trap; Interferon        alfa-2a, rDNA [Interferon alfa-2a-Roferon A; Interferon,        alpha-2a, recombinant]; Interferon alfa-2a, rDNA,        PEG-[Peginterferon alfa-2a-Pegasys; interferon alpha-2a,        recombinant, pegylated]; Interferon alfa-2b, rDNA [Interferon        alfa-2-Intron A; Interferon, alpha-2b, recombinant]; Interferon        alfa-2b, rDNA, PEG-[Peginterferon alfa-2b-PEG-Intron Powder;        interferon alpha-2b, recombinant, pegylated]; Interferon alfa,        rDNA/BioPartners [Interferon alpha, recombinant]; Interferon        alfacon-1, rDNA [Interferon alfacon-1-Infergen; consensus        interferon, recombinant]; Interferon beta-1a, rDNA/Biogen        [Interferon beta-1a-Avonex [recombinant]]; Interferon beta-1a,        rDNA/Serono [Interferon beta-1a-Rebif [recombinant]]; Interferon        betaser, rDNA/Berlex [Interferon beta-1b—Betaseron] (Betaseron        has a MW of 18500 daltons); 2-166-Interferon beta1 (human        fibroblast reduced), 17-L-serine-; interferon betaser,        recombinant]; Interferon gamma, rDNA [Interferon        gamma-1b—Actimmune; [recombinant]]; Interleukin-1ra, rDNA        [Anakinra—Kineret; interleukin-1 receptor antagonist; IL-1i];        Interleukin-2, rDNA [Aldesleukin—Proleukin; des-alanyl-1,        serine-125 interleukin-2, recombinant; IL-2];        Interleukin-2/diphtheria toxin, rDNA [Denileukin diftitox—ONTAK;        Interleukin-2 Fusion Protein; DAB389IL-2;        interleukin-2/diphtheria toxin fusion protein, recombinant]; MRA        (Roche, Chugai), a humanized anti-IL-6 receptor monoclonal        antibody; Interleukin-2 receptor Mab, rDNA/Novartis        [Basiliximab—Simulect; Interleukin-2 alpha receptor monoclonal        antibody, recombinant]; Interleukin-2 receptor Mab, rDNA/Roche        [Daclizumab—Zenapax; Interleukin-2 alpha receptor monoclonal        antibody, recombinant]; Interleukin-11, rDNA        [Oprelvekin—Neumega; des-Pro Interleukin-11, recombinant;        des-Pro IL-11]; IL-6; IL-12; anti-IL-6; and anti-IL-12. As a        general rule, interferons have molecular weights ranging from        15,000 to 21,000 daltons.    -   d. Antibiotics with a molecular weight of 2,000 daltons or        greater;    -   e. Cancer chemotherapeutic agents, with a molecular weight        greater than or equal to 2,000, including those from the        following classes:        -   i. Monoclonal antibodies (mAb): including, but not limited            to:            -   1. Rituximab, a chimeric murine mAb against the CD20                antigen on B-lymphoma cells.            -   2. Epratuzumab, a humanized mouse anti-CD22 mAb.            -   3. Alemtuzumab, a humanized mAb against CD 52 on B and T                lymphoma cells.            -   4. Natalizumab, a humanized mAb against the alpha4                subunit of the alpha4Beta1 and Beta 7 integrins.        -   ii. Conjugates: Monoclonal antibody-drug, -toxin, or            -radionuclide conjugates. These antibodies recognize            specific antigenic determinants on malignant cells and their            conjugates provide selective toxicity to those cells. A            monoclonal antibody conjugate, for the purpose of this            invention, is defined as a monoclonal antibody which is            conjugated to either a drug, a toxin (such as diptheria            toxin) or a radionuclide. These conjugates are particularly            suited to perispinal administration, since they are            extremely effective, even at low concentration, due to their            biologic origin, and can be effectively delivered to the            brain or to a brain tumor or lymphoma via the VVS by            retrograde venous delivery into the brain. Therefore this            class of therapeutic is effective for treating malignant            tumors of the brain, either primary, such as glioblastoma            multiforme, or metastatic, and for treating CNS lymphomas.            These agents include yttrium-90 ibritummomab tiuxetan            (Zevalin®) and iodine-131 tositumomab (Bexxar®) which are            both murine mAbs against CD20 antigen that are conjugated to            a radioactive source and thus selectively deliver radiation            to tumors expressing the CD20 antigen (primarily expressed            on B-lymphomas).

The above methods detailed for large molecules may be used identicallyfor molecules with a MW of less than 2,000 daltons. The rationale fordoing this is that many of these molecules, despite their smaller size,still have difficulty traversing the blood-brain barrier if administeredsystemically; or perispinal delivery without direct intrathecalinjection results in more efficient delivery of these smaller moleculesto the brain, the eye, or the auditory apparatus than does systemic ororal delivery. Perispinal administration and delivery to the brain, theeye, or other structures of the head thereby has the advantage of moreefficient delivery across the BBB. For example the taxanes, whichinclude paclitaxel (Taxol®) and docetaxel (Taxotere®) have very low BBBpenetration when given systemically, despite their respective MW of 854and 862. Doxorubicin has poor BBB penetration when given systemicallydespite its MW of 544. Methotrexate and Amphotericin B have poor BBBpenetration when given systemically, despite a MW of 454 and 924,respectively, and are often administered intrathecally for CNS use. Theperispinal extrathecal methods of the present invention aredistinguished from direct intrathecal injection.

With respect to the small molecules of the present invention, they maybe categorized as follows:

-   -   1. Cancer chemotherapeutic agents, with a molecular weight less        than 2,000, including, but not limited to those from the        following classes: (Clinical use: treatment of tumors of the        central nervous system or the orbit utilizing perispinal        administration without direct intrathecal injection of the        following):        -   i. Alkaloids: vincristine, vinblastine, vindesine,            paclitaxel (Taxol®), docetaxel, etoposide, teniposide.        -   ii. Alkylating agents: nitrogen mustards, nitrosureas,            cyclophosphamide, thiotepa, mitomycin C, dacarbazine.        -   iii. Antibiotics: Actinomycin D, daunorubicin, doxorubicin,            idarubicin, mitoxanthrone, bleomycin, mithramycin.        -   iv. Antimetabolites: methotrexate, 6-mercaptopurine,            pentostatin, 5-fluorouracil, cytosine arabinoside,            fludarabine, 2-CDA.        -   v. Platinum compounds: Cisplatin.        -   vi. Others: tamoxifen (MW 563), flutamide (MW 276),            anastrozole (MW 293), gefitinib (Iressa®) and erlotinib            (Tarceva®) (MW 429).    -   2. Antibiotics: (Clinical use: treatment of bacterial infections        of the central nervous system or the eye utilizing perispinal        administration without direct intrathecal injection of the        following): including, but not limited to cephalosporins,        tetracyclines, macrolides, fluroquinolones.    -   3. Antivirals: (Clinical use: treatment of viral infections of        the central nervous system, particularly meningitis or        encephalitis or the eye utilizing perispinal administration        without direct intrathecal injection of the following):        including, but not limited to oseltamivir, zanamivir,        amantadine, anti-HIV drugs, anti-herpes drugs (including        acyclovir, famciclovir, valacyclovir), anti-CMV drugs        (cidofovir, foscarnet, ganciclovir) and ribavirin.    -   4. Antifungal agents: (Clinical use: treatment of fungal        infections of the central nervous system or the eye utilizing        perispinal administration without direct intrathecal injection        of the following): Amphotericin B and its congeners.    -   5. Anti-parkinson drugs: (Clinical use: treatment of Parkinson's        Disease utilizing perispinal administration without direct        intrathecal injection of the following): including, but not        limited to levodopa, carbidopa, bromocriptine, selegiline, and        dopamine.    -   6. Anti-psychotic agents: (Clinical use: treatment of psychoses,        including schizophrenia, utilizing perispinal administration        without direct intrathecal injection of the following):        haloperidol, Prolixin®, Moban®, Loxitane®, Serentil®, Trilafon®,        Clozaril®, Geodon®, Risperdal®, Seroquel®, and Zyprexa®.    -   7. Antidepressants: (Clinical use: treatment of depression,        including for acute depression as a substitute for        electroconvulsive therapy), utilizing perispinal administration        without direct intrathecal injection of the following):        including, but not limited to tricyclics, tetracyclics,        trazadone, and SSRIs.    -   8. Anticonvulsants: (Clinical use: treatment of seizures,        particularly status epilepticus, utilizing perispinal        administration without direct intrathecal injection of the        following. In addition, please note that these antiepileptic        drugs may also be used for treatment of other CNS disorders,        such as psychoses and depression): including, but not limited        to, Valium®, phenytoin, other hydantoins, barbiturates,        gabapentin, lamotrigine, carbamazepine, topiramate, valproic        acid, and zonisamide.    -   9. Opiates and opioids: (Clinical use: treatment of pain,        including acute pain (e.g. labor and delivery, or field use        following automobile accident, etc.; or chronic pain, as a        substitute for chronic intrathecal drug delivery (e.g. as a        substitute for chronic intrathecal morphine utilizing an        implanted pump), or as a substitute for methadone maintenance        treatment), utilizing perispinal administration without direct        intrathecal injection of the following): including, but not        limited to morphine, oxycodone, other opiates and opioids,        including oxycontin and methadone.

Perispinal extrathecal administration is distinguished from intrathecaladministration because extrathecal administration is both safer (nodural puncture, therefore no risk of CSF leak; less risk of hemorrhage;no risk of spinal cord traumatic injury; less risk of hemorrhage andinfection) and is more effective at delivering the therapeutic moleculeinto the VVS. The dural barrier, once crossed, will contain thetherapeutic molecule within the CSF. CSF flow from the spinal cord tothe brain is slow. In contrast retrograde flow to the brain via the VVSis much more rapid.

For the purposes of this discussion, “perispinal” means in the anatomicvicinity of the spine, but outside of the intrathecal space. For thisdiscussion “anatomic vicinity” is generally defined as within 10centimeters, or functionally defined as in close enough anatomicproximity to allow the therapeutic molecules of consideration herein toreach therapeutic concentration when administered directly to this areawithout necessitating direct intrathecal delivery.

Perispinal administration for delivery of large molecules, includingbiologics, cytokines, anti-cytokines, hormones or drugs via thevertebral venous system, in a manner as outlined herein, may beperformed. The compounds could include interleukins, cytokines,interferons, drugs, growth factors, VEGF inhibitors, monoclonalantibodies, fusion proteins, anti-angiogenic agents, chemotherapeuticagents, cytostatic agents, cancer therapeutics, viral or other vectorsfor delivering gene therapy or other therapeutic molecules for whichdelivery by perispinal administration without direct intrathecalinjection would be beneficial.

One of the advantages of perispinal delivery into the interspinous spaceis that administration is simplified. This route is simple and safe.Hemorrhage due to the use of long or large bore needles is minimizedbecause perispinal administration, by the subcutaneous route, requiresonly a short, narrow bore needle. Time-consuming and difficult epiduralinjection is not necessary. Local perispinal administration also has theadvantage of providing a depot of therapeutic medication in thesurrounding tissue, which will provide therapeutic levels of medicationto the treatment site for a prolonged period of time. This decreases thenecessity for another injection of medication. Additionally,administering medication locally limits the exposure of the medicationto the systemic circulation, thereby decreasing renal and hepaticelimination of the medication, and decreasing exposure of the medicationto systemic metabolism. All of these factors tend to increase thetherapeutic half-life of the administered large molecule. Takentogether, all of these forms of perispinal administration havesignificant clinical advantages over the various forms of systemicadministration customarily used to deliver large molecules systemically.For example, intravenous administration (as conventionally performed, byinfusion into the caval venous system) of infliximab is a systemic routeof administration, as defined herein, and is distinguished fromperispinal administration as a method to reach the brain (predominantlyvia the VVS) as defined herein.

For the sake of this invention, the following definitions also apply:perilesional is defined as in anatomic proximity to the site of thepathologic process being treated; and peridural is defined as inanatomic proximity to the dura of the spinal cord, but specificallyexcluding intrathecal injection. The “interspinous route” for thepurposes of this patent, is defined as parenteral injection through theskin in or near the midline, in the interspace between two spinousprocesses.

This invention is distinguished from the prior art in a variety of ways,including the use and description of novel and useful new uses, methodsof use, and concepts involving large molecules, including:

-   -   1. Novel uses of perispinal administration to enhance delivery        of a large molecule to the brain, the eye, the retina, the        auditory apparatus, the cranial nerves or the head; and    -   2. Novel methods of use of large molecules; and    -   3. Novel concepts, including:        -   a. Perispinal (extrathecal) administration distinguished            from systemic forms of administration and intrathecal            administration;        -   b. The use of the vertebral venous system to deliver large            molecules to the bone brain, the eye, the retina, the            auditory apparatus, the cranial nerves or the head;        -   c. The use of physical maneuvers to facilitate delivery of            therapeutic molecules to the brain, the eye, the retina, the            auditory apparatus, the cranial nerves or the head;        -   d. The use of physical positioning to influence the            direction of venous flow within the vertebral venous system            and thereby deliver therapeutic molecules to the brain, the            eye, the retina, the auditory apparatus, the cranial nerves            or the head;        -   e. The use of retrograde venous perfusion to deliver            therapeutic molecules to the brain, the eye, the retina, the            auditory apparatus, the cranial nerves or the head;        -   f. The use of retrograde venous perfusion via the vertebral            venous system to facilitate delivery of therapeutic            molecules to the brain, the eye, the retina, the auditory            apparatus, the cranial nerves or the head;        -   g. The use of the vertebral venous system as a “back door”            to facilitate delivery of therapeutic molecules to the            brain, the eye, the retina, the auditory apparatus, the            cranial nerves or the head;        -   h. The use of perispinal administration to introduce a large            molecule into the vertebral venous system;        -   i. The use of perispinal administration to efficiently            deliver large molecules to the brain, the eye, the retina,            the auditory apparatus, the cranial nerves or the head.

The same methods described for the named large molecules (such aspegfilgrastim) of this invention also apply to other large moleculeswith a molecular weight of 2,000 daltons or greater, which may be givenby perispinal administration.

A latitude of modification, change, and substitution is intended in theforegoing disclosure, and in some instances, some features of theinvention will be employed without a corresponding use of otherfeatures. Accordingly, it is appropriate that the appended claims beconstrued broadly and in a manner consistent with the spirit and scopeof the invention herein.

(Experimental results compiled by the inventor illustrating the efficacyof perispinal administration of a biologic are described below. Morespecifically, these results illustrate the ability of interspinousinjection to lead to delivery of a biologic to the VVS, and thereafterto the brain, utilizing the methods of the present invention).

Experimental Results

An IRB-approved clinical trial utilizing perispinal etanercept fortreatment of Alzheimer's Disease was begun by the inventor in 2004 andclinical data is available on the first 15 consecutive patients whocompleted more than three weeks of the clinical trial, through Nov. 7,2005, although the clinical trial is ongoing. Data on the 6 monthresults is now available. A summary of the study follows:

Patients

Patients residing in the community, who had previously been diagnosedwith Alzheimer's Disease by a board-certified neurologist and wereclinically declining despite treatment, were recruited, without agerestriction, for inclusion into a six month open-label clinical trialutilizing perispinally administered etanercept. Inclusion required thatthe patient meet the NINCDS-ADRDA Criteria for probable Alzheimer'sdisease[1]; be accompanied by a reliable caregiver; and have apreviously performed MRI or CT scan consistent with a primary diagnosisof AD. All recruited patients also met the DSM-IV criteria for AD[2].Patients were excluded if they had any of the following: activeinfection, multiple sclerosis (or any other demyelinating disorder),pregnancy, uncontrolled diabetes mellitus, tuberculosis, history oflymphoma, or congestive heart failure. In addition, female subjects whowere premenopausal, fertile, or not on acceptable birth control; andpatients with a white blood cell count <2500, hematocrit <30, or aplatelet count<100,000 were excluded. Patients with vascular dementia,clinically significant neurologic disease other than Alzheimer's, or ascore greater than 4 on the modified Hachinski Ischemic Rating Scale[3]were excluded. Additionally, to be eligible for study inclusion, thedosage of all CNS-active medications was required to be unchanged in thefour weeks prior to study initiation and during the entire course of theclinical trial.

Study Design

Patients received etanercept (Immunex Corp.) as a solution in sterilewater given by midline perispinal interspinous injection in theposterior cervical area (as previously described[4]) utilizing a thin(27 gauge) needle, followed by head down Trendelenburg positioning, onceor twice per week, at a total dose ranging from 25 mg to 50 mg per week(0.5-2 cc of solution) on an open-label basis. The initial dose used was25 mg once per week, which was modified as needed. The trial wasapproved by a central institutional review board. The eligible patientsand their responsible caregivers provided written informed consent.

Efficacy Variables

The primary efficacy variables for cognition were three measures: theAlzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog); theSevere Impairment Battery; the Mini-Mental State Examination (MMSE).

Patients were assessed at baseline (treatment day zero) and monthlythereafter. All patients were assessed with the MMSE. Patients with mildand moderate AD were assessed with ADAS-Cog. Patients with severedementia were assessed with the SIB.

Measures of safety included measurement of vital signs and recording ofadverse events.

Results Study Population and Dosage

All data from all 15 patients who completed at least one follow-upevaluation time-point were analyzed. All of these patients completed thefirst six months of treatment. Treatment response data were unavailablefor two patients, in addition to the above 15, who dropped out fornon-medical reasons prior to their first monthly evaluation; these twopatients were excluded from analysis. One patient whose dementia wasborderline between moderate and severe was assessed with both ADAS-Cogand SIB, in addition to MMSE. The baseline characteristics of the 15patient study population are presented in Table 1. The average dosagefor the study cohort was 32±12 mg per week (n=15), and the averagefrequency of dosing was 1.07 times per week.

Statistical Analysis

The main efficacy analysis at 6 months is based on all 15 patients whohave baseline and follow-up data.

The MMSE, ADAS-Cog, and the SIB are considered as the primary outcomemeasures at the end of the three month follow-up assessment. Mixed ModelLinear Regression (MMLR) analyses were used to assess improvement indisease over time, as evaluated by the four outcome measures. In eachanalysis, time (baseline, 1, 2, 3, 4, 5 and 6 months) was entered as afixed variable. The models were also specified with random intercepts,as the participants in this study varied across the spectrum of severityat baseline because recruitment was not limited to a range of severity.Missing data points are treated as missing and are not estimated; thiswas an observed data analysis.

Data were analyzed using statistical analysis software SPSS (Version11.0.3 for Mac OS X, SPSS Inc., Chicago, Ill., USA), with p<0.05indicative of statistical significance.

Efficacy

The results of treatment through six months and the statistical analysisare presented in Table 1.

TABLE 1 Summary of Mixed Model Linear Regression (MMLR) resultsfollowing initiation of perispinal etanercept. Mean Mean Mean Mean MeanMean Baseline change at change at change at change at change at changeat Regression Mean 1 month 2 months 3 months 4 months 5 months 6 monthsAnalyses Measure (n) (SD) (SD) (SD) (SD) (SD) (SD) (SD) Results MMSE(15) 18.2 −.29 +1.07 +1.87 +2.00 +1.93 +2.13 F (1.84) = 39.00, (8.8)(1.82) (2.01) (1.99) (2.13) (2.34) (2.23) p < .001 ADAS-cog (11) 20.85−4.28 −4.64 −4.67 −7.14* −4.52 −5.48 F (1.61) = 11.72, (10.5) (3.44)(4.36) (5.97) (4.51) (4.80) (5.08) p < .002 SIB (5) 62.5 +4.67 +8.2+11.75 +13.6 +13.0 +16.6 F (1.26) = 22.60, (28.05) (6.35) (3.56) (6.45)(10.89) (13.69) (14.52) p < .001 Caption: Baseline raw group mean andstandard deviations are presented with the mean change and SD (eachparticipant compared to their respective baseline performance) for the 6subsequent follow-up months. Note: For the ADAS-Cog, lower scoresindicate clinical improvement. *Note 2: reduced n = 7 at this timepoint. SD = Standard Deviation

TABLE 2 Patient Characteristics, at baseline, prior to perispinaletanercept treatment. Mean ± SD Range Characteristic Age, in yrs. 76.7 ±10.9 52, 94 Female, % (n) 60% (9) — Duration of symptoms, in mos. 43.1 ±37.9  8, 120 ADAS-Cog score (n = 11) 20.8 ± 10.5 7.3, 41  SIB score (n =5)  62.5 ± 28.05 28, 92 MMSE score (n = 15) 18.2 ± 8.8   0, 29 PriorTreatments: Memantine, % (n)  73% (11) — Duration prior to Etanercept,10.6 ± 4.0  1.5, 15  in mos. Donepezil, % (n) 47% (7) — Duration priorto Etanercept, 44.7 ± 47.9  10, 120 in mos. Rivastigmine, % (n) 27% (4)— Duration prior to Etanercept, 5.6 ± 3.3 1, 8 in mos. Galantamine, %(n) 13% (2) — Duration prior to Etanercept, 40.5 ± 6.4  36, 45 in mos.Only 1 of the above, % (n) 40% (6) — Memantine + a cholineserase 60% (9)— inhibitor, % (n)

(End of Experimental Results). PREFERRED EMBODIMENTS

In one preferred embodiment a patient with a clinical disorder involvingthe brain, the retina, the eye, the cranial nerves or hearing is treatedby a perispinal injection of a large molecule, in a therapeuticallyeffective dose, delivered by midline transcutaneous injection overlyingthe spine in the lower posterior neck area, with the patient sitting andhead flexed forward, with immediate placement of the patient in theprone position with the plane of the examination table directed headdownward about 15 degrees after the injection, and maintenance of thepatient in this modified Trendelenburg prone position for severalminutes after injection, in order to deliver the large molecule to thebrain, the retina, the eye, the cranial nerves or the auditory apparatusvia the vertebral venous system, with the dose repeated as a form ofchronic therapy at intervals as often as twice per week to as little asonce per three months.

In another preferred embodiment an individual with a clinical disorderinvolving the eye or retina, who desires to achieve improved vision orto prevent visual loss, is treated by a perispinal injection ofetanercept using a 25 mg dose in solution, delivered by midlinetranscutaneous injection overlying the spine in the lower posterior neckarea, with the patient sitting and head flexed forward, with immediateplacement of the patient in the prone position with the plane of theexamination table directed head downward about 15 degrees after theinjection, and maintenance of the patient in this modified Trendelenburgprone position for several minutes after injection, as either a singledose, or with doses repeated as often as once per week.

In another preferred embodiment injection of a large molecule to theperispinal area is accomplished by percutaneous injection into theanatomic area between two adjacent spinous processes (“the interspinousspace”).

In another preferred embodiment interspinous injection is accomplishedby injection through the skin

Clinical Disorders

-   -   Patients with the following clinical disorders, or in the        following clinical situations, among others, will benefit from        treatment with large molecules delivered by the perispinal route        without direct intrathecal injection:

Macular Degeneration.

This category includes both “wet” or “dry” macular degeneration, both ofwhich involve excess TNF and/or the participation of TNF-mediatedinflammatory or degenerative pathways in their pathogenesis. Treatmentof patients with these disorders with perispinal etanercept leads tovisual improvement and/or slowing of disease progression. Chronictreatment regimens are necessary utilizing perispinal etanercept.Certolizumab pegol or golimumab may be used in a manner which is similarto that of etanercept, except that due to their longer half-life lessfrequent administration, compared to etanercept, is necessary.Etanercept, golimumab, or certolizumab pegol may be administeredconcurrently with memantine (delivered orally) to further reduce retinalinflammation or optic nerve damage. Also soluble TNF receptor type 1,and pegylated soluble TNF receptor type 1 may be administered byperispinal administration for treatment of this disorder. Pegapanib,ranibizumab, and bevacizumab (Avastin™, Genentech), a recombinanthumanized monoclonal IgG1 antibody that binds to and inhibits thebiologic activity of human vascular endothelial growth factor (VEGF),may also be administered by perispinal administration without directintrathecal injection for both the treatment or prevention of maculardegeneration and/or neovascularization and thereby produce visualimprovement or prevention or delay of future visual loss. Additionallythese disorders are known to involve IL-1. Therefore treatment of thesedisorders with an IL-1 antagonist, such as IL-1 RA (Kineret) or IL-1Trap administered by perispinal delivery so that a therapeuticallyeffective dose of the IL-1 antagonist reaches the vertebral venoussystem and thenceforth the retina, delivered utilizing a chronictreatment regimen, is an alternative treatment. Each of these moleculeswill need to be delivered on a chronic basis to decrease theinflammatory response which is responsible for neuronal damage in theseconditions and thereby produce clinical improvement.

Diabetic Retinopathy.

This condition involves excess TNF and/or the participation ofTNF-mediated inflammatory or degenerative pathways in its pathogenesis.Treatment of patients with this disorder with perispinal etanerceptleads to visual improvement and/or slowing of disease progression.Chronic treatment regimens are necessary utilizing perispinaletanercept. Golimumab may be used in a manner which is similar to thatof etanercept, except that due to its longer half-life less frequentadministration, compared to etanercept, will be necessary. Also solubleTNF receptor type 1, and pegylated soluble TNF receptor type 1 may beadministered by perispinal administration for treatment of thisdisorder. Pegapanib, ranibizumab, and bevacizumab (Avastin™, Genentech),a recombinant humanized monoclonal IgG1 antibody that binds to andinhibits the biologic activity of human vascular endothelial growthfactor (VEGF), may also be administered by perispinal administration forboth the treatment or prevention of diabetic retinopathy and/orneovascularization and thereby produce visual improvement or preventionor delay of future visual loss. Additionally these disorders are knownto involve IL-1. Therefore treatment of this disorder with an IL-1antagonist, such as IL-1 RA (Kineret) or IL-1 Trap administered byperispinal delivery so that a therapeutically effective dose of the IL-1antagonist reaches the vertebral venous system and thenceforth theretina, delivered utilizing a chronic treatment regimen, is analternative treatment. Each of these molecules will need to be deliveredon a chronic basis to decrease the inflammatory response which isresponsible for neuronal damage in these conditions and thereby produceclinical improvement.

Glaucoma.

This condition involves excess TNF and/or the participation ofTNF-mediated inflammatory or degenerative pathways in its pathogenesis.Treatment of patients with this disorder with perispinal etanerceptleads to visual improvement and/or slowing of disease progression.Chronic treatment regimens are necessary utilizing perispinaletanercept. Golimumab may be used in a manner which is similar to thatof etanercept, except that due to its longer half-life less frequentadministration, compared to etanercept, will be necessary. Also solubleTNF receptor type 1, and pegylated soluble TNF receptor type 1 may beadministered by perispinal administration for treatment of thisdisorder. Etanercept or golimumab may be administered concurrently withmemantine (delivered orally) to further reduce retinal inflammation oroptic nerve damage. Additionally these disorders are known to involveIL-1. Therefore treatment of this disorder with an IL-1 antagonist, suchas IL-1 RA (Kineret) or IL-1 Trap administered by perispinal delivery sothat a therapeutically effective dose of the IL-1 antagonist reaches thevertebral venous system and thenceforth the retina, delivered utilizinga chronic treatment regimen, is an alternative treatment. Each of thesemolecules will need to be delivered on a chronic basis to decrease theinflammatory response which is responsible for neuronal damage in theseconditions and thereby produce clinical improvement.

Retinitis Pigmentosa.

This condition involves excess TNF and/or the participation ofTNF-mediated inflammatory or degenerative pathways in its pathogenesis.Treatment of patients with this disorder with perispinal etanerceptleads to visual improvement and/or slowing of disease progression.Chronic treatment regimens are necessary utilizing perispinaletanercept. Golimumab may be used in a manner which is similar to thatof etanercept, except that due to its longer half-life less frequentadministration, compared to etanercept, will be necessary. Also solubleTNF receptor type 1, and pegylated soluble TNF receptor type 1, orCertolizumab pegol may be administered by perispinal administration fortreatment of this disorder. Etanercept or golimumab may be administeredconcurrently with memantine (delivered orally) to further reduce retinalinflammation or optic nerve damage. Additionally these disorders areknown to involve IL-1. Therefore treatment of this disorder with an IL-1antagonist, such as IL-1 RA (Kineret) or IL-1 Trap administered byperispinal delivery so that a therapeutically effective dose of the IL-1antagonist reaches the vertebral venous system and thenceforth theretina, delivered utilizing a chronic treatment regimen, is analternative treatment. Each of these molecules will need to be deliveredon a chronic basis to decrease the inflammatory response which isresponsible for neuronal damage in these conditions and thereby produceclinical improvement.

Dementia.

This category includes, but is not limited to Alzheimer's Disease,amnestic mild cognitive impairment, vascular dementia, and mixeddementia. The inventor has clinical experience utilizing etanerceptdelivered by perispinal extrathecal administration demonstratingclinical benefit for each of these conditions. Humans with thesedisorders are amenable to treatment utilizing perispinal administrationwithout direct intrathecal injection of large molecules, including butnot limited to etanercept, golimumab, certolizumab pegol and otheranti-TNF molecules (as illustrated by the experimental results includedherein), MRA (Roche, Chugai), a humanized anti-IL-6 receptor monoclonalantibody; anti-IL-1 molecules; immune globulin (such as IVIG, Baxter,being a mixture of immune globulins, including anti-amyloid antibodies)and other large molecules with immune activity. Golimumab is used byperispinal administration at a dose ranging from 5 mg to 100 mg, with adosing interval from weekly to once per three months. The usual startingdose of golimumab for a human with dementia such as Alzheimer's Diseaseis 10 mg to 25 mg once per two weeks, with dosage titrated as neededwithin the above dosing guidelines.

Malignant Tumors Metastatic to the Spine:

Malignant tumors metastatic to the spine may be treated by the use ofbiologics delivered via the VVS. Access to the VVS may be accomplishedby perispinal administration, in the general manner as described hereinfor etanercept. There is also experimental evidence that bothpro-inflammatory cytokines and their antagonists can be effective in thetreatment of malignancies. This has been demonstrated most clearly withTNF, where high doses have been found to lead to tumor death; and, alsowith TNF blockers that demonstrate a therapeutic benefit in treatingcertain malignancies. This apparent paradox is explained by dose effectswherein a high dosage of TNF may lead to tumor death, whereas a lowdosage may be tumor promoting. Therefore this invention includes any ofthe following molecules used individually: etanercept, golimumab,certolizumab pegol or pegsunercept; and, additionally, includes otherbiologic TNF antagonists, including infliximab, when delivered byperispinal extrathecal administration. The dosage of etanercept for thisapplication ranges from 25 mg to 100 mg; the dosage of golimumab forthis application ranges from 10 mg to 200 mg, and will most often rangebetween 25 mg and 100 mg.

Malignant Intracranial Tumors.

This category includes both primary brain tumors, such as glioblastomamultiforme and tumors metastatic to the brain, all of which involveexcess VEGF and/or the participation of VEGF-mediated angiogenesis, orimmune mechanisms in their pathogenesis. Treatment of patients withthese disorders with perispinal administration without directintrathecal injection of a large molecule which inhibits VEGF; or whichis directly toxic to a tumor, including, but not limited to monoclonalantibodies, or monclonal antibody-antitumor conjugates; or whichotherwise positively affects immune mechanisms; including, but notlimited to such large molecules as etanercept, certolizumab pegol, IL-1Trap, Kineret®, bevacizumab, pegaptanib, ranibizumab, Zevalin®,Mylotarg®, Campath®, HumaSpect®, panitumumab, trastuzumab, Ontak®,Simulect®, Zenapax®, leads to reduced tumor growth, tumor death, and/orslowing of disease progression. CNS lymphomas and other CNS malignanciesmay be treated by perispinal administration without direct intrathecalinjection of rituximab, temozolomide, yttrium-90 ibritummomab tiuxetan,iodine-131 tositumomab, epratuzumab, alemtuzumab, or natalizumab.

Chronic or recurrent treatment regimens may be necessary to deliverthese large molecules to the intracranial tumor via perispinaladministration without direct intrathecal administration. Avoidance ofintrathecal use is safer, has fewer side effects, avoids CSF leak from adural tear, and eliminates the need for chronic intrathecal deliverysystems, such as pumps. Small molecules may also be administered byperispinal delivery without direct intrathecal injection as discussed ina preceding section. Perispinal delivery of small molecules allows theachievement of a higher concentration of the small molecule in the brainand therefore in an intracranial malignant tumor. This is particularlyadvantageous for small molecules which have therapeutic activity for thetreatment of cancer, such as a receptor tyrosine kinase inhibitor.Erlotinib is a small molecule epidermal growth factor receptor (EGFR)inhibitor which is conventionally used for treatment of non-small celllung cancer (NSCLC). Gefitinib is another tyrosine kinase inhibitorwhich may be formulated in solution and therefore delivered byperispinal administration. This invention includes the use of erlotinibin solution, gefitinib in solution, or an erlotinib or gefitinibderivative or other receptor tyrosine kinase inhibitors, given byperispinal administration for treatment of intracranial malignanttumors, including lung cancer metastatic to the brain, or metastases tothe brain of other malignant tumors which overexpress EGFR, or fortreatment of primary brain tumors, including glioblastoma multiforme.Receptor tyrosine kinase is a protein product of the EGFR gene.Inhibition of EGFR-associated tyrosine kinase is a method of treatingsolid tumors, including NSCLC, and perispinal administration of theseagents is a method of the present invention to increase delivery ofthese agents to intracranial tumors. Erlotinib has a MW of 429.Perispinal administration of the molecules of the present inventionleading to delivery of a therapeutically effective amount of saidmolecule to the brain, the eye, or an intracranial tumor isdistinguished from the systemic administration of said molecules.

Multiple Sclerosis.

This immune-mediated disease of the brain is conventionally treated bysystemic administration of Copaxone® (glatiramer acetate), orinterferons, including Avonex®, Rebif®, and Betaseron®. Perispinaladministration of these molecules, and other large molecules, including,but not limited to, rituximab, MRA, Intron A®, PEG-Intron®, Infergen®,and Actimmune® will allow therapeutically effective amounts of theselarge molecules to reach to brain of a human with this disorder, therebyleading to clinical improvement or a decrease in the rate of diseaseprogression.

Hearing Loss.

Hearing loss occurs in humans in many forms. Hearing is essential to thenormal conduct of one's daily activities and people with impairedhearing have many difficulties. Hearing loss can date from birth; it canbe acquired later in life; or it can be the result of trauma, accident,disease, or a toxic effect of a medication. It can be genetic, either asa solitary disorder or as part of a complex syndrome. Hearing loss isone of the most common chronic neurological impairments, estimated toaffect about 4 percent of those under 45 in the United States, and about29 percent of those 65 years or older.

-   -   As defined herein, the neuronal auditory apparatus includes the        cochlea, the auditory division of the eighth cranial nerve, and        the central auditory pathways. Sensorineural hearing loss is one        particular category of hearing loss and is caused by lesions of        the cochlea and/or the auditory division of the eighth cranial        nerve. Prior to this invention, treatment of this condition was        primarily limited to the use of hearing aids.    -   The pathogenetic mechanism of most forms of hearing loss has yet        to be fully defined. The subjects of this patent include central        hearing loss due to lesions of the central auditory pathway;        sensorineural hearing loss; sudden hearing loss; autoimmune        hearing loss; presbycusis; idiopathic hearing loss; and other        forms of hearing loss which are not thought to be primarily due        to disorders of conduction (such as a ruptured tympanic        membrane).    -   Humans react to sounds that are transduced into neurally        conducted impulses through the action of neuroepithelial cells        (hair cells) and spiral ganglion cells (neurons) in the inner        ear. These impulses are transmitted along the cochlear division        of the eighth cranial nerve into the brainstem and the central        auditory pathways.

Presbycusis, or age-related hearing loss, is a type of deafness whichaffects one-third of the population over the age of 75. Presbycusis isknown to be associated with neuronal damage, including loss ofneuroepithelial (hair) cells and associated neurons (see Schuknechtreference). The exact mechanism of presbycusis is unknown, and has longbeen thought to be multifactorial. Inflammation is not widely recognizedas a significant factor in the pathogenesis of presbycusis. Yet aprevious study did suggest that genes encoded by the majorhistocompatibility complex (MHC) had a role in certain hearingdisorders. (Bernstein, Acta Otolaryngol 1996 September; 116(5):666-71).The MHC is known to be central to the immune response and inflammation.Normal hearing is dependant upon proper neuronal function, and may bealtered by autoimmune disorders or other types of inflammation. Theneuronal auditory apparatus is protected by the blood-brain barrier.Therefore delivery of large molecules for therapeutic purposes by thesystemic route is inhibited by the BBB. Delivery of large molecules, inparticular anti-TNF biologics, including golimumab and others, or otherbiologics which reduce inflammation, by perispinal administration, asillustrated herein, is an effective way to treat various types ofhearing loss, including sensorineural hearing loss and presbycusis.

Neuropsychiatric Disorders.

Psychiatric disorders which have a biological basis, such as depressionand schizophrenia, can be treated by the methods of the presentinvention. In particular, humans with these disorders are amenable totreatment utilizing perispinal administration without direct intrathecalinjection of large molecules, including but not limited to anti-TNFmolecules, including golimumab and others (as illustrated by theexperimental results included herein), MRA (Roche, Chugai), a humanizedanti-IL-6 receptor monoclonal antibody; anti-IL-1 molecules; and otherlarge molecules with immune activity.

Brain Disorders.

Brain disorders which have a biological basis, such as seizuredisorders, Huntington's Chorea, Parkinson's Disease, and other braindisorders, can be treated by the methods of the present invention. Inparticular, humans with these disorders are amenable to treatmentutilizing perispinal administration without direct intrathecal injectionof large molecules, including but not limited to anti-TNF molecules,including golimumab and others (as illustrated by the experimentalresults included herein), MRA (Roche, Chugai), a humanized anti-IL-6receptor monoclonal antibody; anti-IL-1 molecules; and other largemolecules with immune activity.

Disc-Related Pain, Including Low Back Pain, Cervical Radiculopathy,Discogenic Pain, Sciatica, and Pain Associated with Degenerative DiscDisease.

The author has considerable experience utilizing perispinal etanerceptfor the treatment of low back pain, discogenic pain, cervicalradiculopathy, sciatica and related disorders which has established theefficacy of this novel method of treatment. Certolizumab pegol andgolimumab given to a human or other mammal by perispinal administrationis also effective for treating these disorders.

Dosages and Routes of Administration

The therapeutically effective dosage of a large molecule used forperispinal administration will in general be 10% to 100% of the dosageused as a single dose for systemic administration. This dosage used forsystemic administration is well known by those skilled in the art as itis specified in the FDA approved literature which accompanies each ofthese biologics, since each is FDA approved for other clinical uses. Forexample, if the usual dose when administered systemically is 50 mg, thenthe dose used for perispinal administration will usually be between 5 mgand 50 mg.

Golimumab may be administered to the perispinal area by interspinousinjection at a dose of 5 mg to 100 mg given from once per week to onceper 3 months. Starting doses of 10 mg-25 mg every other week are givenfor treatment of dementia.

Etanercept may be administered in the perispinal area subcutaneously inthe human and the dosage level is in the range of 10 mg to 100 mg perdose, with dosage intervals as short as one day.

Pegaptanib may be administered perispinally in a therapeuticallyeffective dose. The dosage of pegaptanib may vary from 0.2 mg to 10 mgper dose.

Ranibizumab may be administered in a therapeutically effective dose inthe same ways as detailed for etanercept. The dosage of ranibizumb mayvary from 100 micrograms to 3000 micrograms. For treating ocularneovascularization the most common dosage regimen is 800 micrograms ofranibizumab administered by perispinal injection every 28 days for fourdoses.

It will be appreciated by one of skill in the art that appropriatedosages of the compounds, and compositions comprising the compounds, canvary from patient to patient. The determination of the optimal dosagewill generally involve the balancing of the level of therapeutic benefitagainst any risk or deleterious side effects. The selected dosage levelwill depend on a variety of factors including, but not limited to, theactivity of the particular compound, the route of administration, thetime of administration, the rate of excretion of the compound, theduration of the treatment, other drugs, compounds, and/or materials usedin combination, the severity of the condition, and the species, sex,age, weight, condition, general health, and prior medical history of thepatient. The amount of compound and route of administration willultimately be at the discretion of the physician, veterinarian, orclinician, although generally the dosage will be selected to achievelocal concentrations at the site of action which achieve the desiredeffect without causing substantial harmful or deleterious side-effects.

A latitude of modification, change, and substitution is intended in theforegoing disclosure, and in some instances, some features of theinvention will be employed without a corresponding use of otherfeatures. Accordingly, it is appropriate that the appended claims beconstrued broadly and in a manner consistent with the spirit and scopeof the invention herein.

Definitions provided herein are not intended to be limiting from themeaning commonly understood by one of skill in the art unless indicatedotherwise.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments and optional features, modificationand variation of the inventions embodied therein herein disclosed may beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of this invention.

6. ADVANTAGES OF THE PRESENT INVENTION

Accordingly, an advantage of the present invention is that it providesfor the delivery of a large molecule to the vertebral venous system andthenceforth to the brain, the retina, the eye, the cranial nerves andthe auditory apparatus as a new biologic treatment of humans with aclinical disorder of the brain, the retina, the eye, the cranial nerves,or hearing; such that the use of the biologic will result in clinicalimprovement, or will slow progression of the underlying pathologicprocess.

Accordingly, an advantage of the present invention is that it providesfor the delivery of golimumab to the vertebral venous system andthenceforth to the brain, the retina, the eye, the cranial nerves andthe auditory apparatus as a new biologic treatment of humans with aclinical disorder of the brain, the retina, the eye, the cranial nerves,or hearing; such that the use of golimumab will result in clinicalimprovement, or will slow progression of the underlying pathologicprocess.

Another advantage of the present invention is that it provides for abiologic delivered by perispinal administration, thereby delivering thebiologic into the vertebral venous system and thenceforth the brain, theretina, the eye, the auditory apparatus or the cranial nerves, which,when compared to systemic administration, produces one or more of thefollowing: greater efficacy; more rapid onset; longer duration ofaction; improved delivery to the CNS; or fewer side effects.

Another advantage of the present invention is that it provides for oneof a group of biologics, as specified herein, which affect neuronal orimmune function, delivered by retrograde venous flow through thevertebral venous system into the cranial venous system, therebyfacilitating delivery of the biologic to the brain, the retina, the eye,the cranial nerves and the auditory apparatus for therapeutic purposes.

Accordingly, an advantage of the present invention is that it providesfor the delivery of erlotinib to the vertebral venous system andthenceforth to a malignant intracranial tumor as a new biologictreatment of humans; such that the use of erlotinib will result inclinical improvement, or will slow progression of the cancer.

A latitude of modification, change, and substitution is intended in theforegoing disclosure, and in some instances, some features of theinvention will be employed without a corresponding use of otherfeatures. Accordingly, it is appropriate that the appended claims beconstrued broadly and in a manner consistent with the spirit and scopeof the invention herein.

1. A method for delivering a biologic to a human withAlzheimer's-related dementia, comprising administering said biologicparenterally into the perispinal space of said human without directintrathecal injection, and thereafter positioning said human's headbelow horizontal.
 2. A method for delivering a TNF antagonist to thebrain of a human for treating mild cognitive impairment, Alzheimer'srelated dementia, or vascular dementia, comprising administering the TNFantagonist golimumab parenterally into the perispinal space of saidhuman without direct intrathecal injection, and thereafter positioningsaid human in a Trendelenburg position, for delivery of said golimumabto the brain via the human's vertebral venous system.
 3. A method fordelivering a biologic to a human, comprising administering said biologicparenterally into the perispinal space of said human without directintrathecal injection.
 4. The method of claim 1, wherein said biologicis etanercept.
 5. The method of claim 1, wherein said biologic isgolimumab.
 6. The method of claim 1, wherein said biologic is Gammagard.7. The method of claim 1, wherein said biologic is bapineuzumab.
 8. Themethod of claim 2, further comprising positioning said human's headbelow horizontal to facilitate gravity assisted retrograde flow ofgolimumab to the brain.
 9. The method of claim 3, wherein said human hasneck pain.
 10. The method of claim 3, wherein said human has cervicalradiculopathy.
 11. The method of claim 3, wherein said human hasdegenerative disc disease.
 12. The method of claim 3, wherein said humanhas fibromyalgia.
 13. The method of claim 3, wherein said human hasneuropathic pain.
 14. The method of claim 3, wherein said human hassciatica.
 15. The method of claim 3, wherein said human has low backpain.
 16. The method of claim 3, wherein the human has sciatica, and thebiologic is an anti-TNF-alpha therapeutic molecule.
 17. The method ofclaim 3, wherein the human has sciatica, and the biologic is etanercept.18. The method of claim 3, wherein the biologic is etanercept.
 19. Themethod of claim 1, wherein said administered biologic bypasses theblood-brain barrier to reach the brain.
 20. The method of claim 3,wherein said biologic is selected from the group of etanercept,certolizumab pegol, IL-1 Trap, Kineret®, bevacizumab, pegaptanib,ranibizumab, rituximab, Zevalin®, Mylotarg®, Campath®, HumaSpect®,abatacept, cetuximab, panitumumab, pegfilgrastim, filgrastim,erythropoietin, Aranesp®, trastuzumab, Pegasys®, Intron A®, PEG-Intron®,Infergen®, Avonex®, Rebif®, Betaseron®, Actimmune®, Ontak®, Simulect®,Zenapax®, Genkaxin®, recombinant human growth hormone, reteplase,alteplase, tPA (tissue plasminogen activator), urokinase plasminogenactivator, streptokinase, urokinase, or immune globulin), Tarceva®,bapineuzumab, Gammagard™, or IVIG.